N-(heterocyclyl)benzene or pyridinesulphonamides as antithrombotic agents and anticoagulants

ABSTRACT

Compounds of formula [I]                   
     in which: 
     W may represent a —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH 2 —C≡C— or —CH 2 —CH═CH— group, 
     R 2  may in particular represent a piperidyl group, an optionally substituted 1,2,3,6-tetrahydropyridyl group, a hexahydro-1H-azepinyl group, an optionally substituted piperazinyl group or a morpholinyl group, 
     R 3  may in particular represent a group —COR 1 , 
     A may in particular represent an optionally substituted phenyl group, a heterocycle or a cyclopentyl group, and 
     B may in particular represent a pyridyl group, an aminopyrazinyl group, an aminopyridazinyl group, a pyrimidinyl group optionally substituted with an amino group, piperidyl group or an aminopyridyl group optionally substituted on the pyridine with a (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy group, the amino group possibly also being substituted with a (C 1 -C 4 )alkyl group, 
     their preparation and their therapeutic application.

The present invention relates to N-(heterocyclyl)benzene- or-pyridinesulphonamide derivatives, to their preparation and to theirtherapeutic application.

The compounds of the present invention correspond to formula [I]:

in which:

X represents either a group ═CR₄— or a nitrogen atom,

W represents a —(CH₂)₂—, —(CH₂)₃—, —CH₂—C≡C— (triple bond) or—CH₂—CH═CH— (double bond in cis or trans configuration) group,

R₂ represents

either a piperidyl group which is optionally substituted:

with one or two groups chosen from hydroxyl, (C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl and(C₃-C₆)cycloalkyl group,

with a group ═CYZ [Y and Z being chosen, independently of each other,from hydrogen atoms, halogen atoms and (C₁-C₄)alkyl groups (optionallysubstituted with 1 to 3 halogen atoms)],

with a group:

 (r=1 to 3) or

with a spiro[(C₃-C₆)cycloalkane] group,

or a 1,2,3,6-tetrahydropyridyl group optionally substituted with a(C₁-C₄)alkyl group (this (C₁-C₄)alkyl group being optionally substitutedwith 1 to 3 halogen atoms) or a (C₃-C₆)cycloalkyl group,

or a hexahydro-1H-azepinyl group optionally substituted in position 4with a trifluoromethyl or difluoromethylene group,

or a heptahydroazocin-1-yl group,

or an octahydro-1H-azonin-1-yl group,

or a group

 (a-b being a group —CONR′—, m=1 to 2, p=1 to 2 and

R′ is a hydrogen atom or a (C₁-C₄)alkyl group),

or a group

 in which

either R₁₂ is a (C₁-C₄)alkyl group, a carboxy(C₁-C₄)alkyl group or a(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl group and R₁₃ is a (C₁-C₄)alkoxy or(C₁-C₄)alkyl group, or R₁₂ is a (C₁-C₄)alkyl or —CH₂CF₃ group and R₁₃ isa

group

 (Q being a carbon or nitrogen atom and r=1 to 3),

or a piperazinyl group optionally substituted with a (C₁-C₄)alkyl groupor a (C₁-C₄)alkylsulphonyl group,

or a morpholinyl group,

R₄ represents

either a halogen atom,

or a hydrogen atom,

R₃ represents

either a (C₁-C₅)alkyl group,

or a group —COR₁, in which R₁ is either a hydrogen atom or a group(C₁-C₄)alkyl, —(CH₂)_(n)OCH₃, —CH₂O(C₂H₄O)_(n)CH₃, —(CH₂)_(n)CF₃ or—(CH₂)_(n)OH (n=1 to 4),

or a group —SO₂R₅,

or a group —CONHR₅,

or a group —SO₂N(R₅)₂, in which R₅ is a (C₁-C₄)alkyl group,

A represents

either a phenyl group optionally substituted with 1 to 3 substituentschosen from

a halogen atom and

groups (C₁-C₄)alkyl, (C₁-C₄)alkoxy, trifluoromethyl, trifluoromethoxy,—CH₂OR₁₀, —CH₂OCOR₁₀, —CH₂OCONR₁₀R₁₁, —COOR₁₀, —CONR₁₀R₁₁, nitro,—NR₁₀R₁₁, —NHCOR₁₀ and —NH(CH₂)_(q)OR₁₀, in which R₁₀ and R₁₁ are,independently of each other, a hydrogen atom or a (C₁-C₄)alkyl group andq is between 0 and 6,

or a heterocycle chosen from pyridyl, thienyl, furyl, pyrimidinyl andthiazolyl groups, the said groups possibly being substituted like thephenyl group above,

or a (C₅-C₈)cycloalkyl group, and B represents

either a pyridyl group optionally substituted with 1 or 2 substituentschosen from a (C₁-C₄)alkyl group, a hydroxyl group and a (C₁-C₄)alkoxygroup,

or an aminopyrazinyl group,

or an aminopyridazinyl group,

or a pyrimidinyl group optionally substituted with an amino group,

or a piperidyl group,

or an aminopyridyl group optionally substituted on the pyridine with a(C₁-C₄)alkyl or (C₁-C₄)alkoxy group or a halogen atom, the amino grouppossibly also being substituted with a (C₁-C₄)alkyl group,

or an aminophenyl group, the amino group possibly being substituted witha (C₁-C₄)alkyl group and the phenyl group possibly being substitutedwith a (C₁-C₄)alkyl group or a halogen atom.

In the context of the invention, the terms below have the followingmeanings:

a (C₁-C₄)alkyl group is a linear or branched, saturatedhydrocarbon-based chain containing from 1 to 4 carbon atoms,

a (C_(x)-C_(y))cycloalkyl group is a cyclic hydrocarbon-based chaincontaining from x to y carbon atoms,

a (C₁-C₄)alkoxy group is an oxygen radical substituted with a(C₁-C₄)alkyl group defined above,

a halogen atom is a chlorine, bromine, iodine or fluorine atom.

In the context of the invention, the halogen atoms are preferablychlorine, fluorine and bromine.

Depending on the nature of the group W, the compounds of formula (I) inaccordance with the invention may be represented by formulae (I₁), (I₂),(I₃) and (I₄) below:

The compounds that are preferred according to the invention are thecompounds of formula [I] in which:

X, W, R₄, A and B are as defined above,

R₂ represents

either a piperidyl group which is optionally substituted:

with one or two groups chosen from hydroxyl, (C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, monofluoromethyl, difluoromethyl, trifluoromethyl and(C₃-C₆) cycloalkyl groups,

with a group ═CYZ [Y and Z being chosen, independently of each other,from hydrogen atoms, halogen atoms and (C₁-C₄)alkyl groups (optionallysubstituted with 1 to 3 halogen atoms)],

or a 1,2,3,6-tetrahydropyridyl group optionally substituted with a(C₁-C₄)alkyl group (this (C₁-C₄)alkyl group being optionally substitutedwith 1 to 3 halogen atoms) or a (C₃-C₆)cycloalkyl group,

or a hexahydro-1H-azepinyl group optionally substituted in position 4with a trifluoromethyl or difluoromethylene group,

or a group

 in which

R₁₂ is a (C₁-C₄)alkyl group, a carboxy(C₁-C₄)alkyl group or a(C₁-C₄)alkoxycarbonyl (C₁-C₄)alkyl group and R₁₃ is a (C₁-C₄)alkoxy or(C₁-C₄)alkyl group,

or a piperazinyl group optionally substituted with a (C₁-C₄)alkyl groupor a (C₁-C₄)alkylsulphonyl group,

or a morpholinyl group,

R₃ represents

either a (C₁-C₅)alkyl group,

or a group —COR₁, in which R₁ is either a hydrogen atom or a group(C₁-C₄)alkyl, —(CH₂)_(n)OCH₃, —CH₂O(C₂H₄O)_(n)CH₃, —(CH₂)_(n)CF₃ or—(CH₂)_(n)OH (n=1 to 4).

Among the preferred compounds defined above, the ones that areparticularly preferred are the compounds of formula [I] in which:

X, R₄ and B are as defined above,

W represents a —(CH₂)₃— or —CH₂—CH═CH— (double bond in cis or transconfiguration) group,

R₂ represents

either a piperidyl group which is optionally substituted:

with one or two groups chosen from hydroxyl, (C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, monofluoromethyl, difluoromethyl and trifluoromethylgroups,

with a group ═CYZ [Y and Z being chosen, independently of each other,from hydrogen atoms, halogen atoms and (C₁-C₄)alkyl groups (optionallysubstituted with 1 to 3 halogen atoms)],

or a 1,2,3,6-tetrahydropyridyl group optionally substituted with a(C₁-C₄)alkyl group (this (C₁-C₄)alkyl group being optionally substitutedwith 1 to 3 halogen atoms),

or a hexahydro-1H-azepinyl group,

or a piperazinyl group optionally substituted with a(C₁-C₄)alkylsulphonyl group,

or a morpholinyl group,

R₃ represents a group —COR₁, in which R₁ is a group (C₁-C₄)alkyl,—(CH₂)_(n)OCH₃ or —(CH₂)_(n)CF₃ (n=1 to 4),

A represents

either a phenyl group optionally substituted with 1 to 3 substituentschosen from

a halogen atom and

(C₁-C₄)alkyl and (C₁-C₄)alkoxy groups,

or a heterocycle chosen from pyridyl and thienyl groups,

or a (C₅-C₈)cycloalkyl group.

The preferred configuration of the central amino acid portion of thecompounds in accordance with the present invention:

is [S]

The compounds of formula [I] in accordance with the invention may existin the form of racemates or pure enantiomers or mixtures of enantiomers.They may also exist in the form of acids or free bases or addition saltswith pharmaceutically acceptable acids, for example in the form ofhydrochloride or methanesulphonate.

Mention may be made in particular of the following compounds, in theform of racemates or pure enantiomers or mixtures of enantiomers, oralternatively in the form of acids or free bases, of hydrochloride or ofany other pharmaceutically acceptable salt, which form a part of theinvention:

N-[2-[[[(1S)-4-(5-amino-3-methylpyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,

N-[2-[[[(1S)-4-(6-amino-4-ethylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]propanamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]acetamide,

N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-piperid-1-yl-carbonyl)butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,

N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-yl-phenyl]acetamide,

N-[2-[[[(1S)-4-(6-amino-4-methylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide,

N-[2-[[[(1S)-4-(aminopyrid-3-yl)-1-[[4-(trifluoromethyl)-1,2,3,6-tetrahydropyrid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-yl-phenyl]propanamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]propanamide,

N-[2-[[[(1S)-4-(6-amino-4-methylpyrid-3-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,

N-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]propanamide,

N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]acetamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,

N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methyl[1,1′-diphenyl]-2-yl]acetamide,

N-[3-[[[(1S)-4-(6-amino-4-methoxypyrid-3-yl-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]propanamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methyl[1,1′-diphenyl]-2-yl]propanamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]acetamide,

N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methoxy[1,1′-diphenyl]-2-yl]propanamide,

N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3′-methyl[1,1′-diphenyl]-3-sulphonamide,

N-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide,

N-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[(4-methyl-1-piperidyl)carbonyl]-3-butenyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide.

A subject of the invention is also a medicinal product, characterized inthat it contains at least one compound of formula (I) as defined above.

A subject of the invention is also a pharmaceutical composition,characterized in that it contains at least one compound of formula (I)as defined above, as well as at least one pharmaceutically acceptableexcipient.

With reference to Scheme 1, in order to obtain the compounds of formula[I] in accordance with the present invention in which X represents agroup ═CR₄—, a compound of formula [V] in which P₁ is a protecting groupfor an amine function, in particular a tert-butoxycarbonyl (Boc) group,B and W are as defined above and P is either a protecting group such asphenylmethoxycarbonyl or a hydrogen atom, is reacted, in a step (i),with a compound of formula [VI], in which R₂ is as defined above. Acompound of formula [IV] is thus obtained, which is treated withhydrogen chloride in a step (ii) to give a compound of formula [III].

In a step (iii), the compound of formula [III] is coupled, in thepresence of triethylamine, with a compound of formula [II] in which R₁,R₄ and A are as defined above, to give, after treatment with ammonia, acompound of formula [I]. The modification of the group —NHCOR₁ into agroup —NHR₃ as defined above in relation to formula [I] is carried outaccording to the techniques of organic chemistry that are known to thoseskilled in the art.

When it is desired to obtain a compound of formula [I] in which R₄ is ahydrogen atom, a hydrogenolysis of compound [I] is then carried out in astep (iv) to give a compound of formula [Ib].

According to one preferred embodiment of the process for preparing thecompounds of formula (I) of the present invention,

the step (i) mentioned above may be carried out in the presence ofN,N-diisopropylethylamine (DIEA) in dichloromethane or indimethylformamide by adding, under nitrogen,O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU),

step (ii) may be carried out in dichloromethane in the presence ofhydrogen chloride gas,

step (iii) may be carried out first in dichloromethane and triethylamine(TEA) and then by taking up the product obtained in tetrahydrofuran(THF) and then passing a stream of ammonia through, followed bytreatment with 0.1 N hydrogen chloride in isopropanol, or with hydrogenbromide in acetic acid,

step (iv) may be carried out by taking up the compound of formula [I] ina 0.1 N solution of hydrogen chloride and in isopropanol.

According to one variant of the process in accordance with the presentinvention, the compounds of formula [I], in which X represents a group═CR₄—, are also prepared in accordance with Scheme 2. With reference toScheme 2, these compounds may be prepared by reacting, in a step (i),the compound of formula [III] as obtained in step (ii) of the process ofthe invention described above (Scheme 1) [with P=a hydrogen atom] with acompound of formula [IIa], in which R₄ is a halogen atom and R₁ is asdefined above. A compound of formula [Ia] is thus obtained, which iscoupled with a compound of formula [VII] in which A is as defined aboveand R₅ is a (C₁-C₄)alkyl group, to give a compound of formula [I]. Whenit is desired to obtain a compound of formula [I] in which R₄ is ahydrogen atom, a hydrogenolysis of compound [I] is then carried out in astep (iii) to give a compound of formula [Ib].

According to one preferred embodiment of this variant of the process forpreparing the compounds of formula [I] of the present invention, inwhich X represents a group ═CR₄—,

step (i) mentioned above may be carried out first in dichloromethane, inthe presence of triethylamine, and then by next taking up the productobtained in a stream of ammonia,

step (ii) may be carried out in a mixture of copper iodide andtriphenylarsine (Ph₃As) in anhydrous dimethylformamide (DMF) and byadding bisdibenzylideneacetonepalladium (0) [Pd(dba)₂],

step (iii) may be carried out in the presence of activepalladium-on-charcoal (Pd-c), and ammonium formate in methanol,

step (iv) may be carried out by taking up the compound of formula [I] ina 0.1 N solution of hydrogen chloride and in isopropanol.

The compounds of formula [V] of the present invention, as represented inScheme 1, are prepared according to Schemes 3 and 4.

Schemes 3 and 4 illustrate the preparation of various types of compoundsof formula [V], namely:

the compound of formula [Ve], which is useful as an intermediate in thepreparation of compounds of formula (I) in which W=CH₂—CH═CH— (thedouble bond being in cis configuration),

the compound of formula [Vg], which is useful as an intermediate in thepreparation of compounds of formula (I) in which W=—CH₂—CH═CH— (thedouble bond being in trans configuration),

the compound of formula [Vh], which is useful as an intermediate in thepreparation of compounds of formula (I) in which W=—(CH₂)₃—,

the compound of formula [Vc], which is useful as an intermediate in thepreparation of compounds of formula (I) in which W=CH₂—C≡C—,

the compound of formula [Vi], which is useful as an intermediate in thepreparation of compounds of formula (I) in which W=—(CH₂)₂—.

To prepare the compound of formula [Vc], the following steps are carriedout, for example (Scheme 3):

in a step (i), and by analogy with the synthesis disclosed in patentapplication WO 97/40052, a compound of formula [Va] in which P₁ is asdefined above, is reacted with a compound of formula [Vb] in which B₁ isan aromatic base bearing either a protected or unprotected primary orsecondary amine function, or a precursor of an amine function such as anitro group, and X represents a halogen atom, to give a compound offormula [Vc].

To convert the compound of formula [Vc] into a compound of formula [V]which may be used directly in the process represented in Scheme 1, asaponification of the ester group is carried out, and, when B₁ bears aprecursor of an amine function, this precursor is converted into anamine group optionally protected with a group P, by means of thetechniques of organic chemistry that are known to those skilled in theart.

To prepare the compound of formula [Vh], the following steps are carriedout, for example (Scheme 3):

in step (ii), the compound of formula [Vc] is subjected either to atotal hydrogenation, both of the triple bond and of the nitrogenheterocycle, optionally followed by a conventional orthogonal protectionof the non-aromatic secondary amine which may be generated, with a groupP such as phenylmethoxycarbonyl, or to a selective hydrogenation of thetriple bond, followed by a saponification, to give the compound offormula [Vh].

To prepare the compound of formula [Ve], the following steps are carriedout, for example (Scheme 3):

in a step (iii), compound [Vc] is subjected to a controlledhydrogenation of the triple bond, optionally followed by a conventionalorthogonal protection of the secondary amine of the amine borne by thegroup B, with a group P such as tert-butoxycarbonyl (Boc). In a step(iv), a saponification of the ester group of compound [Vd] is carriedout to give compound [Ve].

To prepare the compound of formula [Vg], the following steps are carriedout, for example (Scheme 3):

in a step (v), compound [Va] is subjected first to a hydrostannylationof the triple bond, followed by a catalysed coupling via a palladiumcomplex with a compound [Vb] in which B₁ is an aromatic base bearingeither a protected or unprotected primary or secondary amine function,or a precursor of an amine function such as a nitro group, and Xrepresents a halogen atom, to give the compounds of formula [Vf],

in a step (vi), the ester group of the compound [Vf] is hydrolysed togive the compound of formula [Vg].

According to one preferred embodiment of the process for preparing thecompounds of formula [V] of the present invention, as illustrated inScheme 3:

step (i) mentioned above may be carried out in dimethylformamide, in thepresence of a palladium-based catalyst such as thedichlorobis(triphenylphosphine)palladium/cuprous iodide complex, inbasic medium, for example with potassium bicarbonate and in anhydrousdimethylformamide,

step (ii) mentioned above may be carried out with molecular hydrogen orammonium formate, in methanol, in the presence of a palladium-basedcatalyst such as active palladium-on-charcoal, and by carrying out thesaponification with lithium hydroxide in a methanol/water mixture,

step (iii) mentioned above may be carried out in the presence ofpalladium on barium sulphate in ethyl acetate. When B1 bears a nitrofunction, it is desirable to reduce it beforehand, preferably with ironin an ethanol/acetic acid mixture,

step (iv) leading to the compounds [Ve] may be carried out with lithiumhydroxide in a methanol/water mixture,

step (v) may be carried out with a compound [Va] bearing a protectinggroup P1 such as trityl in order to improve the regioselectivity of thehydrostannylation reaction. This is carried out with tributyltin hydridein tetrahydrofuran in the presence oftetrakis(triphenylphosphine)palladium (0). The coupling with theelectrophilic reagent [Vb] is carried out in anhydrous dioxane in thepresence of tetrakis(triphenylphosphine)palladium (0),

when the group P₁ of the compound of formula [Vf] is a trityl, step (vi)consists in converting the group P₁ of trityl type into atert-butyloxycarbonyl group in the presence of aqueous sodium hydroxideusing bis(di-tert-butyl) carbonate. In this operation, the methyl esteris hydrolysed to carboxylic acid, thus giving the compound of formula[Vg].

With reference to Scheme 4, the intermediate compounds of formula [Vi]may be prepared, thus making it possible to prepare the compounds offormula [I] in which W is a —(CH₂)₂— group, in the following way:

in a step (i), a compound of formula [VII] derived from glutamic acid,in which P₁ is as defined above and Ph represents a phenyl group, issubjected to a Hunsdiecker reaction to give the compound of formula[VIII],

in a step (ii), the compound of formula [VIII] is converted into thecorresponding organozinc derivative, which is coupled in situ, viacatalysis with palladium, to a compound of formula [Vb] in which B₁ isas defined above and X represents a halogen atom, to give the compoundsof formula [IX],

in a step (iii), the compound of formula [IX] is hydrogenated on apalladium catalyst to give the compound of formula [Vi] bearing a freecarboxylic acid function.

According to one preferred embodiment of this process for preparing thecompounds of formula [Vi] of the present invention,

step (i) mentioned above may be carried out in carbon tetrachlorideunder argon, in the presence of di(acetyloxy)iodobenzene and moleculariodine. This step is thus carried out under UV irradiation,

step (ii) mentioned above may be carried out in dimethylformamide underargon in the presence of zinc powder activated by adding trimethylsilylchloride and 1,2-dibromoethane. The organozinc derivative thus preparedis then treated with the electrophile B₁X, for example in the presenceof tris(dibenzylideneacetone)dipalladium and tri-ortho-tolylphosphine atroom temperature,

step (iii) mentioned above may be carried out in a methanol/watermixture in the presence of active 10% palladium-on-charcoal catalyst andat 50 psi of hydrogen.

With reference to Scheme 5, in order to obtain the compounds of formula[XV], which are useful as intermediates for preparing the compounds offormula [I] in accordance with the invention in which X=N, the followingsteps are carried out:

in a step (i), a 4-aminopyridine compound of formula [X] in which theamine function is protected with a protecting group P1 as defined above,is converted into a derivative of formula [XI] bearing two bromine atomspositioned beforehand to introduce the desired groups,

in a step (ii), the compound of formula [XI] is coupled with a boronicacid derivative of formula AB(OH)₂ in which A is a phenyl nucleus or aheterocycle which is optionally substituted, in the presence of apalladium catalyst, to give a compound of formula [XII],

in a step (iii), the sulphur atom which is the precursor of thesulphonyl chloride group is introduced via a palladium-catalysedcoupling reaction between the compound of formula [XII] and an organotinderivative prepared beforehand from benzenemethanethiol,

in a step (iv), the protecting group P₁ is removed by acidic treatmentunder conventional conditions to give the compound of formula [XIV],

in a step (v), the compound of formula [XIV] is converted into a mixedimide by treatment with an anhydride, and the benzylthiol group is thendirectly oxidized to the chlorosulphonyl derivative of formula [XV] withsulphuryl chloride in the presence of acetic acid and water.

According to one preferred embodiment of this process for preparing thecompounds of formula [XV]:

step (i) mentioned above may be carried out in acetonitrile withN-bromosuccinimide,

step (ii) mentioned above may be carried out in a dioxane/water mixturein the presence of sodium carbonate andtetrakis(triphenylphosphine)palladium (0),

step (iii) mentioned above may be carried out in anhydrous dioxane inthe presence of tetrakis(triphenylphosphine)palladium (0) withtributyl[(phenylmethyl)thio]stannane prepared beforehand,

step (iv) mentioned above may be carried out conventionally in methanolin the presence of a stream of hydrogen chloride,

step (v) mentioned above may be carried out by heating in a pureanhydride such as propionic anhydride. After evaporating off the excessreagent, a treatment in a mixture of acetic acid and water withsulphuryl chloride gives the expected chlorosulphonyl compound offormula [XV] directly.

The compound of formula [XV] thus obtained may then be used to preparethe compounds of formula [I] in accordance with the invention in whichX=N, by following the protocol described in step (iii) of Scheme 1, i.e.by coupling the compound of formula [XV] with a compound of formula[III] as defined above.

The starting compounds, such as the compound of formula [Vb] arecommercially available or are described in the literature, oralternatively may be prepared according to methods which are describedtherein or which are known to those skilled in the art.

The examples which follow illustrate the preparation of certaincompounds in accordance with the invention. The microanalyses and the IRand NMR spectra confirm the structure of the compounds obtained.

The numbers for the compounds illustrated refer to those in the tablesgiven later, which illustrate the chemical structures and physicalproperties of a number of compounds according to the invention. Theratio (x:y) represents the (acid:base) ratio.

EXAMPLE 1 (COMPOUND 3)(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-yl-phenyl]propanamidehydrochloride

1.1. N-(5-bromopyrid-2-yl)-2,2,2-trifluoroacetamide

68.0 ml (0.477 mol) of a solution of trifluoroacetic anhydride in 250 mlof dichloromethane are added dropwise at 0° C., under nitrogen, to asolution of 75.0 g (0.433 mol) of 5-bromo-2-pyridinamine and 41.25 ml(0.519 mol) of pyridine in 250 ml of dichloromethane. The mixture isallowed to warm gently to room temperature and stirring is continued for18 hours. The reaction mixture is diluted with 300 ml of dichloromethaneand is then washed with water (2×400 ml) and then in saturated sodiumchloride solution (2×200 ml), after which it is dried over sodiumsulphate and concentrated under reduced pressure. The residue obtainedis purified by chromatography on a column of gel, eluting under pressurewith a dichloromethane/pentane (1:1) mixture. 100 g ofN-(5-bromopyrid-2-yl)-2,2,2-trifluoroacetamide are obtained in the formof a white solid.

Yield (%)=86; m.p. (°C.)=73.

1.2. Methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[6-[(trifluoroacetyl)amino]pyrid-3-yl]pent-4-ynoate

1.7 g (2.4 mmol) of dichlorobis(triphenylphosphine)palladium are addedat room temperature, under argon, to a mixture of 13.0 g (48.3 mmol) ofN-(5-bromo-2-pyridyl)-2,2,2-trifluoroacetamide, 16.0 g (70.5 mmol) ofmethyl (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate, 0.46 g(2.4 mmol) of copper iodide and 13.35 g (96.6 mmol) of potassiumcarbonate in 25 ml of anhydrous dimethylformamide (DMF). The mixture isheated for 5 hours at 65° C. The mixture is taken up in ether (800 ml)and then washed with water (2×600 ml) and then with saturated sodiumchloride solution (300 ml) and is dried over sodium sulphate. Theproduct obtained is filtered and then concentrated under reducedpressure. The residue obtained is purified by chromatography on a columnof silica gel, eluting under pressure with an ethyl acetate/cyclohexanegradient of from 0 to 20% ethyl acetate. 10 g of methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino-5-[6-(trifluoroacetyl)amino]pyrid-3-yl]pent-4-ynoateare thus obtained in the form of an oil.

Yield (%)=52

1.3.(S)-6-Amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-3-pentanoicacid

A mixture of 8.04 g of methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-[6-(trifluoroacetyl)amino]pyrid-3-yl)pent-4-ynoate(20 mmol) and active 10% palladium-on-charcoal (0.8 g) in methanol (80ml) and acetic acid (1.32 ml; 22 mmol) is stirred for 7 hours under 50psi of hydrogen at room temperature. The mixture is filtered and is thenconcentrated under reduced pressure. The residue obtained is taken up inethyl acetate (400 ml) and then washed with saturated sodium hydrogencarbonate solution (200 ml) and saturated sodium chloride solution (200ml), filtered and dried over sodium sulphate and is then concentratedunder reduced pressure. Lithium hydroxide monohydrate (1.1 g, 26 mmol)is added, at 0° C., to a solution of the residue thus obtained inmethanol (50 ml) and water (15 ml). The mixture is allowed to warm toroom temperature and stirring is continued for 18 hours. The reactionmixture is cooled to 0° C., neutralized with 1N hydrochloric acidsolution and then concentrated under reduced pressure. 7 g of(S)-6-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-3-pentanoicacid (lithium chloride) are obtained in the form of a viscous oil, whichis used without further purification in the following step.

Yield (%)=88

1.4. 1,1-Dimethylethyl(S)-[4-(6-aminopyrid-3-yl)-1-([4-ethylpiperid-3-yl)carbonyl]butyl]carbamate

2.1 g (5.5 mmol) of O-(benzotriazol-1l-yl)-N,N,N′, N′-tetramethyluroniumhexafluorophosphate (HBTU) are added portionwise with stirring, at 0° C.under nitrogen, to a mixture of 2.0 g of(S)-6-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-3-pentanoicacid (5.5 mmol), 1.14 g (7.5 mmol) of 4-ethylpiperidine hydrochloride,N,N-diisopropylethylamine (DIEA) (25 ml; 14 mmol) in dichloromethane (30ml) and 3 ml of anhydrous dimethylformamide (DMF). The mixture isallowed to warm to room temperature and stirring is continued for 18hours. The reaction mixture is taken up in 250 ml of ethyl acetate andis washed with 50 ml of 0.1 N hydrochloric acid solution and with 50 mlof saturated sodium hydrogen carbonate solution and with 50 ml ofsaturated sodium chloride solution. The product obtained is then driedover sodium sulphate and then filtered and concentrated under reducedpressure. The residue obtained is purified by chromatography on a columnof silica gel, eluting under pressure with ethyl acetate. 1.48 g of1,1-dimethylethyl(S)-[4-(6-aminopyrid-3-yl)-1-([4-ethylpiperid-3-yl)carbonyl]butyl]carbamateare obtained in the form of a viscous oil.

Yield (%)=74

1.5. (S)-1-[2-Amino-5-(6-aminopyrid-3-yl)-1-oxopentyl]-4-ethylpiperidinehydrochloride (2:1)

A solution of 1.48 g (3.6 mmol) of 1,1-dimethylethyl(S)-[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]carbamatein 40 ml of dichloromethane is treated for 1 min at 0° C. with a streamof hydrogen chloride. After one hour at 0° C., the reaction mixture isallowed to warm to room temperature and is then concentrated underreduced pressure. 1.4 g of(S)-1-[2-amino-5-(6-aminopyrid-3-yl)-1-oxopentyl]-4-ethylpiperidinehydrochloride (2:1) are obtained in the form of a white solid, which isused without further purification in the following step.

Yield (%)=100; m.p. (°C.)=65.

1.6.(S)-N-[2-[[[4-(6-aminopyrid-3-yl)]-1-(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamidehydrochloride

1.84 ml (13.2 mmol) of triethylamine (TEA) are added, at 0° C., to asolution of 1.5 g (4 mmol) of(S)-1-[2-amino-5-(6-aminopyrid-3-yl)-1-oxopentyl]-4-ethylpiperidinehydrochloride (2:1) in 20 ml of dichloromethane, followed by portionwiseaddition of 1.54 g (4 mmol) of2-[bis(1-oxopropyl)amino]-3-thien-2-ylbenzenesulphonyl chloride. After 4h at 0° C., 200 ml of ethyl acetate are added and the mixture is thenwashed with 100 ml of saturated sodium hydrogen carbonate solution and100 ml of saturated sodium chloride solution. The product obtained isdried over sodium sulphate and concentrated under reduced pressure. Theresidue thus obtained is taken up in 100 ml of tetrahydrofuran (THF) andis then cooled to 0° C. and treated for 5 minutes with a stream ofammonia. The reaction mixture is allowed to warm to room temperatureand, after 4 hours, is then concentrated under reduced pressure. Theresidue obtained is taken up in 50 ml of a 0.1N solution of hydrogenchloride in isopropanol (5 mmol) and is then concentrated under reducedpressure and purified by chromatography on an RP 18 column, eluting withan acetonitrile/water gradient of from 5/95 to 30/70. 2 g of(S)-N-[2-[[[4-(6-aminopyrid-3-yl)]-1-(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamidehydrochloride are obtained.

Yield (%)=79; m.p. (°C.)=144-148;

[α]_(D) ²⁰ (°)=+120 (c=0.2; methanol)

EXAMPLE 2 (COMPOUND 5)(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-pyrid-2-yl-phenyl]propanamidehydrochloride (2:1)

2.1.(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-iodophenyl]propanamide

The same procedure as in Example 1.6 is used, except for the treatmentwith a 0.1N solution of hydrogen chloride in isopropanol and thepurification by chromatography on an RP18 column. Thus, starting with1.4 g (3.6 mmol) of(S)-1-[2-amino-5-(6-aminopyrid-3-yl)-1-oxopentyl]-4-ethylpiperidinehydrochloride (2:1) and 1.88 g (3.6 mmol) of2-[bis(1-oxopropyl)amino]-5-bromo-3-iodobenzenesulphonyl chloride, 1.9 gof(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-iodophenyl]propanamideare obtained in the form of a white powder.

Yield (%)=81; m.p. (°C.)=193.

2.2.(S)-N-[2-[[[4-(6-Aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-pyrid-2-ylphenyl]propanamide

0.08 g (0.14 mmol) of bis(dibenzylideneacetone)palladium (0) is added,at room temperature, to a mixture of 1.8 g (2.76 mmol) of(S)-N-[2-[[[4-(6-aminopyrid-3-yl)]-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-iodophenyl]propanamide,1.22 g (3.32 mmol) of 2-(tributylstannyl)pyridine, 0.052 g (0.28 mmol)of copper iodide and 0.17 g (0.56 mmol) of triphenylarsine in 6 ml ofanhydrous dimethylformamide (DMF). The reaction mixture is heated at 80°C. for 7 hours and is then taken up in 200 ml of ethyl acetate. Themixture is then washed twice with 200 ml of aqueous 10% ammonia solutionand then with 100 ml of water and 100 ml of saturated sodium chloridesolution. The resulting solution is dried over sodium sulphate andfiltered and the resulting product is concentrated under reducedpressure. The residue thus obtained is purified by chromatography on acolumn of silica gel, eluting under pressure with a 94/6dichloromethane/methanol mixture. 0.54 g of(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-pyrid-2-ylphenyl]propanamideis obtained in the form of an oil.

Yield (%)=30

2.3.(S)-N-[2-[[[4-(6-Aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-pyrid-2-ylphenyl]propanamidehydrochloride (2:1)

A mixture of 0.2 g (0.3 mmol) of(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-4-bromo-6-pyrid-2-ylphenyl]propanamide,0.02 g of active 10% palladium-on-charcoal and 0.2 g of ammonium formate(3.0 mmol) in 10 ml of methanol is refluxed for 2 h. The reactionmixture is filtered and is then taken up in 100 ml of dichloromethane,washed with 50 ml of saturated sodium hydrogen carbonate solution and 50ml of saturated sodium chloride solution. The resulting solution isdried over sodium sulphate and then filtered and the resulting productis concentrated. The residue thus obtained is taken up in 40 ml of a0.1N solution of hydrogen chloride in isopropanol and is thenconcentrated and purified by chromatography on an RP18 column, elutingwith an acetonitrile/water gradient of from 5/95 to 30/70. 0.135 g of(S)-N-[2-[[[4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-3-yl)carbonyl]butyl]amino]sulphonyl]-6-pyrid-2-ylphenyl]propanamidehydrochloride (2:1) is obtained.

Yield (%)=75; m.p. (°C.)=145-150;

[α]_(D) ²⁰ (°)=+138; (c=0.2; methanol)

EXAMPLE 3 (COMPOUND 10)(S)-N-[2-[[[1-[(4-Ethylpiperid-3-yl)carbonyl]-4-piperid-3-ylbutyl]amino]sulphonyl]-6-thien-2-yl-phenyl]propanamidehydrochloride

3.1. Methyl(S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoate

A mixture of 2.8 g (10.0 mmol) of methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-pyrid-4-ylpent-4-ynoateand 0.28 g of active 10% palladium-on-charcoal in 20 ml of ethanol isstirred for 3 hours at room temperature under 60 psi of hydrogen. Thereaction mixture is filtered and concentrated under reduced pressure.The residue obtained is taken up in 20 ml of acetic acid and stirred for14 hours in the presence of 0.05 g of platinum oxide, under 60 psi ofhydrogen. The reaction mixture is filtered and then concentrated underreduced pressure. The residue obtained is taken up in 10 ml oftetrahydrofuran (THF) and 5 ml of water. This solution is cooled to 0°C., followed by addition of a solution of 3.4 g (40.0 mmol) of sodiumhydrogen carbonate in 40 ml of water, and 1.63 ml (12.0 mmol) of benzylchloroformate are added dropwise. The mixture is allowed to warm to roomtemperature and the reaction is continued for 4 hours. The reactionmixture is taken up in 200 ml of ethyl acetate and is washed twice with100 ml of 1N hydrochloric acid solution and then with 100 ml ofsaturated sodium hydrogen carbonate solution and with 100 ml ofsaturated sodium chloride solution. The resulting solution is dried oversodium sulphate. The resulting product is filtered and concentrated. Theresidue obtained is purified by chromatography on a column of silicagel, eluting under pressure with a cyclohexane/ethyl acetate gradient offrom 95/5 to 80/20. 3.55 g of methyl(S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoateare obtained in the form of a viscous oil.

Yield (%)=79; mp (°C.)=110.

3.2.(S)-α-[[(1,1-Dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoicacid

A mixture of 3.55 g (8.0 mmol) of methyl(S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoateand 0.40 g (9.6 mmol) of lithium hydroxide monohydrate in 15 ml ofmethanol and 5 ml of water is stirred for 18 h at room temperature. Themethanol is evaporated off under reduced pressure and the mixture isthen cooled to 0° C. and acidified to pH 2 with aqueous 1N hydrochloricacid solution, and then extracted twice with 150 ml of ethyl acetate.The resulting extract is washed with 100 ml of saturated sodium chloridesolution and then dried over sodium sulphate and filtered, and theresidue obtained is concentrated. 3 g of(S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]piperidine-4-pentanoicacid are obtained in the form of a white powder, which is used withoutfurther purification in the following step.

Yield (%)=86

3.3. Phenylmethyl(S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylate

1.7 g (4.4 mmol) of O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HBTU) are added portionwise, at 0° C. undernitrogen, to a solution of 1.73 g (4.0 mmol) of(S)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-1-[(phenylmethoxy)carbonyl]-piperidine-4-pentanoicacid, 0.66 g (4.4 mmol) of 4-ethylpiperidine hydrochloride and 1.8 ml(10.4 mmol) of N,N-diisopropylethylamine (DIEA) in dichloromethane. Thereaction mixture is allowed to warm slowly to room temperature and thereaction is continued for 18 hours. The reaction mixture is then takenup in 200 ml of ethyl acetate and is washed with 100 ml of 1Nhydrochloric acid solution and then with 100 ml of saturated sodiumhydrogen carbonate solution and with 100 ml of saturated sodium chloridesolution. The resulting product is dried over sodium sulphate and isfiltered and then concentrated. The residue obtained is purified bychromatography on a column of silica gel, eluting under pressure with a4/6 ethyl acetate/cyclohexane mixture. 2 g of phenylmethyl(S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylateare obtained in the form of a viscous oil.

Yield (%)=95

3.4. Phenylmethyl(S)-4-[4-amino-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylatehydrochloride

A solution of 1.54 g (3.0 mmol) of phenylmethyl(S)-4-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylatein 60 ml of dichloromethane is treated for 5 min at 0° C. with a streamof hydrogen chloride. After 3 hours at 0° C., the mixture isconcentrated under reduced pressure. The resulting product is usedwithout further purification in the following step. 1.35 g ofphenylmethyl(S)-4-[4-amino-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylatehydrochloride are thus obtained in the form of a viscous oil.

Yield (%)=100

3.5.(S)-N-[2-[[[1-[(4-Ethylpiperid-3-yl)carbonyl]-4-piperid-4-ylbutyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamidehydrochloride

1.27 g (3.3 mmol) of2-[bis(1-oxopropyl)amino]-3-thien-2-ylbenzenesulphonyl chloride areadded portionwise, at 0° C., to a solution of 1.35 g (3.0 mmol) ofphenylmethyl(S)-4-[4-amino-5-(4-ethylpiperid-1-yl)-5-oxopentyl]piperidine-1-carboxylatehydrochloride and 0.96 ml (6.9 mmol) of triethylamine (TEA) in 15 ml ofdichloromethane. The mixture is allowed to warm slowly to roomtemperature and the reaction is continued for 18 hours. The reactionmixture is taken up in 250 ml of ethyl acetate and is washed with 100 mlof 1N hydrochloric acid solution and with 100 ml of saturated sodiumhydrogen carbonate solution and with 100 ml of saturated sodium chloridesolution. The resulting product is dried over sodium sulphate and isfiltered and then concentrated under reduced pressure. The residueobtained is taken up in 100 ml of tetrahydrofuran (THF) and is cooled to0° C. and then treated for 5 minutes with a stream of ammonia. Themixture is allowed to warm to room temperature. After 4 hours, thereaction mixture is concentrated under reduced pressure. The residueobtained is taken up in 250 ml of ethyl acetate, washed with 50 ml of 1Nhydrochloric acid solution and then with 50 ml of saturated sodiumhydrogen carbonate solution and with 50 ml of saturated sodium chloridesolution. The resulting product is dried over sodium sulphate andfiltered and then concentrated under reduced pressure. The residueobtained is taken up in 1.2 ml of acetic acid, cooled to 0° C. and thentreated with a 5N solution of hydrogen bromide in 1.2 ml of acetic acid,added dropwise. The mixture is allowed to warm to room temperature.After 4 hours, the reaction mixture is concentrated under reducedpressure. The residue obtained is taken up in 250 ml of ethyl acetateand is washed with 50 ml of saturated sodium hydrogen carbonate solutionand then with 50 ml of saturated sodium chloride solution. The resultingproduct is dried over sodium sulphate and filtered and is thenconcentrated after addition of a 0.1N solution of hydrogen chloride in40 ml of isopropanol. The residue obtained is purified by chromatographyon an RP18 column, eluting with an acetonitrile/water gradient of from5/95 to 30/70. 0.36 g of(S)-N-[2-[[[1-[(4-ethylpiperid-3-yl)carbonyl]-4-piperid-4-ylbutyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamidehydrochloride is obtained.

Yield (%)=22; m.p. (°C.)=134-138;

[α]_(D) ²⁰ (°)=+112 (c=0.2; methanol)

EXAMPLE 4 (COMPOUND 24)(S)-N-[3-[[[4-(5-Aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]propanamidehydrochloride

4.1. Methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(5-nitropyrid-2-yl)pent-4-ynoate

A mixture of 2-bromo-5-nitropyridine (10.0 g; 49.0 mmol), methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate (13.34 g; 58.8mmol), copper iodide (0.465 g; 2.5 mmol), potassium carbonate (13.6 g;98.0 mmol) and dichlorobis(triphenylphosphine)palladium (1.7 g; 2.5mmol) in 30 ml of anhydrous dimethylformamide (DMF) is heated for 4hours at 60° C. under argon. The reaction mixture is taken up in 800 mlof ethyl acetate, washed with 2×400 ml of water, 400 ml of saturatedhydrogen carbonate and 400 ml of brine, dried over sodium sulphate,filtered and then concentrated under reduced pressure. The residueobtained is purified on a column of silica, eluting with acyclohexane/ethyl acetate gradient of from 0 to 20% ethyl acetate. 11 gof methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(5-nitropyrid-2-yl)pent-4-ynoateis isolated.

Yield (%)=65

4.2. Methyl(S)-5-amino-α-[[1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoate

A mixture of methyl(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(5-nitropyrid-2-yl)pent-4-ynoate(10.5 g; 30.0 mmol), ammonium formate (19.0 g; 300.0 mmol) and active10% palladium-on-charcoal (1.1 g) in 100 ml of methanol is refluxed for3 hours under argon. The reaction mixture is filtered and thenconcentrated under reduced pressure. The residue obtained is taken up in400 ml of ethyl acetate, washed with 100 ml of brine, dried over sodiumsulphate, filtered and then concentrated under reduced pressure. Theresidue is purified on a column of silica, eluting with adichloromethane/methanol (96/4) mixture. 6.5 g of methyl(S)-5-amino-α-[[1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoateare isolated in the form of a viscous oil.

Yield (%)=62

4.3.(S)-5-Amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoicacid

Lithium hydroxide monohydrate (0.9 g; 21.1 mmol) is added, at 0° C., toa mixture of methyl(S)-5-amino-α-[[1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoate(6.2 g; 17.6 mmol) in 45 ml of methanol and 15 ml of water. The mixtureis allowed to warm slowly to room temperature and stirring is continuedfor 18 hours. The reaction mixture is cooled to 0° C., neutralized with1N hydrochloric acid (22.0 ml; 22.0 mmol) and then concentrated underreduced pressure. 7.0 g of(S)-5-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoicacid are isolated in the form of an amorphous powder.

Yield (%)=100

4.4. 1,1-Dimethylethyl(S)-[4-(5-aminopyrid-2-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamate

The same procedure as in Example 1.4 is used, except for thepurification on a column of silica, which is carried out with acyclohexane/ethyl acetate gradient of from 50% to 100% ethyl acetate.Thus, starting with(S)-5-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoicacid (3.14 g; 8.0 mmol) and 4-(difluoromethylene)piperidinehydrochloride (1.63 g; 9.6 mmol), 2.45 g of 1,1-dimethylethyl(S)-[4-(5-aminopyrid-2-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamateare isolated in the form of a white solid.

Yield (%)=72; m.p. (°C.)=142

4.5.(S)-1-[2-Amino-5-(5-aminopyrid-2-yl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride

The same procedure as in Example 1.5. is used. Thus, starting with1,1-dimethylethyl(S)-[4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamate(2.4 g; 5.6 mmol), 2.25 g of(S)-1-[2-amino-5-(5-aminopyrid-2-yl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride are obtained in the form of a hygroscopic amorphouspowder, which is used without further purification in the followingstep.

Yield (%)=100

4.6.(S)-N-[3-[[[4-(5-aminopyrid-2-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro-[1,1′-diphenyl]-2-yl]propanamidehydrochloride

The same procedure as in Example 1.6 is used, with the exception of thepurification on an RP18 column, which is carried out using awater/acetonitrile gradient of from 0 to 40% acetonitrile. Thus,starting with(S)-1-[2-amino-5-(5-aminopyrid-2-yl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride (0.65 g; 1.6 mmol) and[2-(bis(1-oxopropyl)amino]-3′-fluoro-1,1′-diphenyl]-3-yl]sulphonylchloride (0.69 g; 1.6 mmol), 0.69 g of(S)-N-[3-[[[4-(5-aminopyrid-2-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro-[1,1′-diphenyl]-2-yl]propanamidehydrochloride is isolated.

Yield (%)=65; m.p. (°C.)=136-140;

[α]_(D) ²⁰ (°)=+90 (c=0.2; methanol)

EXAMPLE 5 (COMPOUND 6)(S)-N-[2-[[[4-(5-Amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamidehydrochloride

5.1. 5-Bromo-2-pyrazinamine

28.2 g of N-bromosuccinimide (0.158 mol) are added portionwise, at 0°C., to a solution of 2-aminopyrazine (15.0 g, 0.158 mol) in 900 ml ofdichloromethane. After 3 hours, the reaction mixture is filtered througha sinter funnel, washed with saturated sodium carbonate (2×400 ml),water (400 ml) and brine (200 ml), dried over sodium sulphate, filteredand concentrated under reduced pressure. The residue obtained ispurified on a column of silica eluted under pressure with acyclohexane/ethyl acetate gradient (9/1) to (1/1). 18.0 g of5-bromo-2-pyrazinamine are obtained in the form of a yellowish powder.

Yield (%)=66; m.p. (°C.)=144

5.2. Methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate

The process is performed in the same way as in Example 1.2., andstarting with 7.5 g (43.0 mmol) of 5-bromo-2-pyrazinamine and 11.71 g(51.6 mmol) of methyl(S)-2-[[1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoate, to give, after7 h at room temperature, 10.6 g of methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pent-4-ynoatein the form of a viscous oil.

Yield (%)=77

5.3. Methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-pentanoate

A mixture of methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-pent-4-ynoate(10.0 g; 31.2 mmol), ammonium formate (29.7 g; 468.0 mmol) and active10% palladium-on-charcoal (1.2 g) in methanol (100 ml) is refluxed for 3hours. The reaction mixture is filtered and concentrated under reducedpressure. The residue obtained is taken up in ethyl acetate (300 ml),washed with brine (2×200 ml), dried over sodium sulphate, filtered andconcentrated under reduced pressure. The residue obtained is purified ona column of silica eluted under pressure with a dichloromethane/methanolmixture (96/4). 7.9 g of methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoateare isolated in the form of a viscous oil.

Yield (%)=79

5.4.(S)-5-(5-Amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoicacid

Lithium hydroxide (1.2 g, 28.6 mmol) is added, at 0° C., to a solutionof methyl(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate(7.75 g, 23.9 mmol) in methanol (60 ml) and water (20 ml). The mixtureis allowed to warm to room temperature and stirring is continued for 18hours. The methanol is evaporated off under reduced pressure and theresidue obtained is cooled to 0° C., acidified to pH 3-4 with 1Nhydrochloric acid (30 ml), extracted with ethyl acetate (2×200 ml),washed with brine (50 ml), dried over sodium sulphate, filtered andconcentrated under reduced pressure. 7.17 g of(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoicacid are obtained in the form of a white powder, which is used withoutfurther purification in the following step.

Yield (%)=97; m.p. (°C.)=76.

5.5. 1,1-Dimethylethyl(S)-[4-(5-amino-2-pyrazinyl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamate

The process is performed in the same way as in Example 1.4, and startingwith 2.32 g (7.5 mmol) of(S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoicacid and 1.9 g (11.25 mmol) of 4-(difluoromethylene)piperidinehydrochloride, to give 2.61 g of 1,1-dimethylethyl(S)-[4-(5-amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl)carbonyl]butyl]carbamatein the form of an amorphous powder.

Yield (%)=82; m.p. (°C.)=133

5.6.(S)-1-[2-Amino-5-(5-amino-2-pyrazinyl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride (2:1)

The process is performed in the same way as in Example 1.5., andstarting with 2.6 g (6.1 mmol) of 1,1-dimethylethyl(S)-[4-(5-amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamate,to give 2.45 g of(S)-1-[2-amino-5-(5-amino-2-pyrazinyl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride (2:1) in the form of a viscous oil.

Yield (%)=100

5.7.(S)-N-[2-[[[4-(5-Amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamidehydrochloride

The process is performed in the same way as in Example 1.6, and,starting with 1.11 g (3.0 mmol) of2-[bis(1-oxopropyl)amino]-3-cyclopentylbenzenesulphonyl chloride and1.21 g (3.0 mmol) of(S)-1-[2-amino-5-(5-amino-2-pyrazinyl)-1-oxopentyl]-4-(difluoromethylene)piperidinehydrochloride (2:1), 1.3 g of(S)-N-[2-[[[4-(5-amino-2-pyrazinyl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamideare obtained.

Yield (%)=68; m.p. (°C.)=136-140;

[α]_(D) ²⁰ (°)=+103 (c=0.2; methanol)

EXAMPLE 6 (COMPOUND 71)N-[3-[[[(1S)-4-(5-Aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamidehydrochloride

6.1. 2-(Diacetylamino)[1,1′-diphenyl]-3-sulphonyl chloride

A solution of the N,N-diethylethanamine salt of2-amino[1,1′-diphenyl]-3-sulphonic acid (31.2 g; 89.0 mmol) in aceticanhydride (93.0 ml) is refluxed for 4 hours. The reaction mixture isconcentrated under reduced pressure. The residue obtained is taken up indichloromethane (250.0 ml) and cooled to 0° C., followed by addition ofphosphorus pentachloride (37.40 g; 178.0 mmol). After 6 hours at 0° C.,the reaction mixture is concentrated under reduced pressure. The residueobtained is taken up in ether (500 ml), washed with brine (100 ml),dried over sodium sulphate, filtered and then concentrated. The residueis chromatographed on a column of Florisil®, eluting with ann-hexane/ether gradient of from 0 to 60% ether. 14.1 g of2-(diacetylamino)[1,1′-diphenyl]-3-sulphonyl chloride are isolated inthe form of an amorphous white solid.

Yield (%)=45.0

6.2. 1,1-Dimethylethyl[(S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]carbamate

The same procedure as in Example 1.4 is used, with the exception of thepurification on a column of silica, which is carried out with an ethylacetate/methanol gradient of from 0 to 10% methanol. Thus, starting with(S)-5-amino-α-[[(1,1-dimethylethoxy)carbonyl]amino]pyridine-2-pentanoicacid (11.0 g; 31.0 mmol) and 4-methylpiperidine (5.5 ml; 46.0 mmol),1,1-dimethylethyl[(S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]carbamateare isolated.

Yield (%)=86

6.3.1-[(2S)-2-Amino-5-(5-aminopyrid-2-yl)-1-oxopentyl]-4-methylpiperidinehydrochloride

The same procedure as in Example 1.5 is used. Thus, starting with1,1-dimethylethyl[(S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]carbamate(10.2 g; 26.0 mmol), 9.5 g of1-[(2S)-2-amino-5-(5-aminopyrid-2-yl)-1-oxopentyl[-4-methylpiperidinehydrochloride are obtained in the form of a hygroscopic amorphouspowder, which is used without further purification in the followingstep.

Yield (%)=100

6.4.N-[3-[[[(1S)-4-(5-Aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide

The process is performed in the same way as in Example 1.6. Thus,starting with 2-(diacetylamino)[1,1′-diphenyl]-3-sulphonyl chloride(4.57 g; 13.0 mmol) and1-[(2S)-2-amino-5-(5-aminopyrid-2-yl)-1-oxopentyl]-4-methylpiperidinehydrochloride, 5.2 g ofN-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl][1,1-diphenyl]-2-yl]acetamideare obtained.

Yield (%)=66; m.p. (°C.)=176-180;

[α]_(D) ²⁰ (°)=+184 (c=0.2; methanol)

EXAMPLE 7 (COMPOUND 52)N-[[[3-[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamidehydrochloride

The process is performed in the same way as in Example 1.6. Thus,starting with 3.52 g (10.0 mmol) of2-(diacetylamino)[1,1′-diphenyl]-3-sulphonyl chloride and 4.2 g (10.5mmol) of 1,1-dimethylethyl(S)-[4-(5-aminopyrid-2-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]carbamate,4.5 g ofN-[[[3-[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamideare obtained.

Yield (%)=71; m.p. (°C.)=170-174;

[α]_(D) ²⁰ (°)=+90 (c=0.2; methanol)

EXAMPLE 8 (COMPOUND 114)N-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-5-phenylpyrid-4-yl]propanamidehydrochloride

8.1 1,1-Dimethylethyl (3,5-dibromopyrid-4-yl)carbamate

A mixture of 1,1-dimethylethyl 4-pyridinecarbamate (11.0 g; 57.0 mmol)and N-bromo-succinimide (25.6 g; 142.0 mmol) in acetonitrile (50 ml) isheated for 12 hours at 55° C. The reaction mixture is concentrated underreduced pressure. The residue obtained is taken up in ether (400 ml),washed with saturated aqueous potassium bicarbonate solution (2×200 ml),dried over sodium sulphate, filtered and then concentrated under reducedpressure. The residue is chromatographed on a column of silica, elutingwith an ethyl acetate/cylohexane gradient of from 0 to 10% ethylacetate. 8.2 g of 1,1-dimethylethyl (3,5-dibromopyrid-4-yl)carbamate areisolated in the form of a white solid.

Yield (%)=41

8.2 1,1-Dimethylethyl (3-bromo-5-phenylpyrid-4-yl)carbamate

A mixture of 1,1-dimethylethyl (3,5-dibromo-4-pyridyl)carbamate (4.2 g;12.0 mmol), phenylboronic acid (1.76 g; 14.4 mmol), sodium carbonate(3.1 g; 29.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.416g; 0.36 mmol) in dioxane (24 ml) and water (12 ml) is heated at 70° C.under argon for 8 hours. The reaction mixture is concentrated underreduced pressure. The residue obtained is taken up in ethyl acetate (200ml), washed with water (2×100 ml) and brine (100 ml), dried over sodiumsulphate, filtered and then concentrated under reduced pressure. Theresidue is chromatographed on a column of silica, eluting with an ethylacetate/cyclohexane gradient of from 0 to 5%. 2.3 g of 1,1-dimethylethyl(3-bromo-5-phenylpyrid-4-yl)carbamate are isolated in the form of awhite solid.

Yield (%)=55

8.3 Tributyl[(phenylmethyl)thio]stannane

1,8-Diazabicyclo[5.4.0.]undec-7-ene (DBU) is added dropwise at 20° C.,under argon, to a solution of benzenemethanethiol (11.72 ml; 100.0 mmol)in anhydrous DMF (20.0 ml). After 0.5 hour at 20° C., the reactionmixture is cooled to 0° C. and tributyltin chloride is added dropwise.The mixture is allowed to warm to room temperature and stirring iscontinued for 5 hours. The reaction mixture is taken up in pentane (400ml), washed with water (3×300 ml) and brine (100 ml), washed with sodiumsulphate, filtered and then concentrated under reduced pressure. 39.0 gof tributyl[(phenylmethyl)thio]stannane are obtained in the form of acolourless oil, which is used without further purification in thefollowing step.

Yield (%)=95

8.4 1,1-Dimethylethyl[3-phenyl-5-[(phenylmethyl)thio]pyrid-4-yl]carbamate

A mixture of 1,1-dimethylethyl (3-bromo-5-phenylpyrid-4-yl)carbamate(2.30 g; 6.6 mmol), tributyl[(phenylmethyl)thio]stannane (2.44 ml; 7.3mmol) and tetrakis(triphenylphosphine)palladium (0) (0.30 g; 0.26 mmol)in anhydrous dioxane (4.0 ml) is heated for 10 hours under argon at 90°C. After 4 hours and 6 hours, tetrakis(triphenylphosphine)palladium (0)is added (0.30 g and 0.15 g, respectively). The reaction mixture istaken up in ether (100 ml), treated for 0.5 hour with aqueous 5%potassium fluoride solution (50 ml) and then filtered through a sinterfunnel. The filtrate is washed with brine (50 ml), dried over sodiumsulphate, filtered and then concentrated without reduced pressure. Theresidue obtained is chromatographed on a column of silica, eluting withan ethyl acetate/cyclohexane gradient of from 0 to 20% ethyl acetate.1.0 g of1,1-dimethylethyl[3-phenyl-5-[(phenylmethyl)thio]pyrid-4-yl]carbamateare isolated in the form of a white solid.

Yield (%)=45

8.5 3-Phenyl-5-[(phenylmethyl)thio]pyrid-4-amine

A solution of 1,1-dimethylethyl[3-phenyl-5-[(phenylmethyl)thio]pyrid-4-yl]carbamate (0.9 g; 2.7 mmol)in methanol (50 ml) is treated for 5 minutes at 0° C. with a stream ofhydrogen chloride. The mixture is allowed to warm to room temperatureand stirring is continued for 6 hours. The reaction mixture isconcentrated under reduced pressure. The residue obtained is taken up inethyl acetate (150 ml), treated with saturated aqueous potassiumcarbonate solution (20 ml), dried over sodium sulphate and filtered andthen concentrated under reduced pressure. 0.8 g of3-phenyl-5-[(phenylmethyl)thio]pyrid-4-amine is obtained in the form ofa viscous oil, which is used without further purification in thefollowing step.

Yield (%)=100

8.6 4-[bis(1-oxopropyl)amino]-5-phenylpyrid-3-sulphonyl chloride

A solution of 3-phenyl-5-[(phenylmethyl)thio]pyrid-4-amine (0.8 g; 2.74mmol) in propionic anhydride is heated at 150° C. for 6 hours. Thereaction mixture is concentrated under reduced pressure and used withoutfurther purification in the following step. Sulphuryl chloride (0.75 ml;9.4 mmol) is added dropwise, at 5° C., to a mixture of the crude productobtained above in acetic acid (3 ml) and water (0.2 ml). After 0.5 hourat 5° C., the reaction mixture is concentrated under reduced pressure.The residue obtained is taken up in ether (150 ml), washed with water(50 ml) and brine (50 ml), dried over sodium sulphate, filtered and thenconcentrated under reduced pressure. 1.1 g of4-[bis(1-oxopropyl)amino]-5-phenylpyrid-3-sulphonyl chloride areobtained in the form of a viscous oil, which is used without furtherpurification in the following step.

Yield (%)=100

8.7N-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-5-phenylpyrid-4-yl]propanamidehydrochloride

A solution of 4-[bis(1-oxopropyl)amino]-5-phenylpyrid-3-sulphonylchloride (0.5 g; ˜1.0 mmol) in dichloromethane (3 ml) is added dropwise,at 0° C., to a mixture of1-[(2S)-2-amino-5-(6-aminopyrid-3-yl)-1-oxopentyl]-4-methylpiperidine(0.35 g; 1.1 mmol) and triethylamine (0.45 ml; 3.3 mmol) indichloromethane (3 ml). After 6 hours at 0° C., the reaction mixture istaken up in ethyl acetate (100 ml), washed with brine (50 ml), driedover sodium sulphate, filtered and then concentrated under reducedpressure. The residue obtained is taken up in tetrahydrofuran (20.0 ml),cooled to 0° C. and then treated for 5 minutes with a stream of ammoniagas. After 4 hours at room temperature, the reaction mixture isconcentrated under reduced pressure. The residue is chromatographed on acolumn of silica, eluting with a dichloromethane/methanol gradient offrom 0 to 5% methanol. 0.45 g of base is isolated (yield (%)=77), whichis taken up in 2 ml of a 0.1N solution of hydrogen chloride inisopropanol and is concentrated under reduced pressure. The residue ispurified by chromatography on a column of RP18 silica gel, eluting witha 3/7 acetonitrile/water mixture. 0.42 g ofN-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-5-phenylpyrid-4-yl]propanamidehydrochloride is isolated.

Yield (%)=66; m.p. (°C.)=180-184;

[α]_(D) ²⁰ (°)=+100 (c=0.2; methanol)

EXAMPLE 9 (COMPOUND 118) [1,1′-diphenyl]-3-sulphonamide,N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3′-methylhydrochloride

9.1[1,1′-diphenyl]-3-sulphonamide-2-amino-N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]butyl]-3′-methyl

0.74 ml of triethylamine (5.31 mmol) is added dropwise to a stirredsolution of 0.64 g (1.77 mmol) of(1S)-5-amino-α-[[4-difluoromethylene)-1-piperidyl]carbonyl]-2-pyridinebutanaminedihydrochloride in 10 ml of dichloromethane, followed by dropwiseaddition, at 0° C., of a solution of2-amino-3′-methyl-[1,1-diphenyl]-3-sulphonyl chloride (0.50 g; 1.77mmol) in 2 ml of dichloromethane. After stirring for 16 h at roomtemperature, the reaction medium is evaporated under reduced pressure.The residue is taken up in 100 ml of ethyl acetate and washed with 25 mlof saturated sodium bicarbonate solution and then with 25 ml ofsaturated sodium chloride solution and finally dried over Na₂SO₄. Thesolvent is evaporated off under reduced pressure and the residue ischromatographed on silica in a dichloromethane/methanol mixture of from0 to 10% methanol, to give 0.6 g of pure product.

Yield (%)=60

9.2N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3′-methyl[1,1′-diphenyl]-3-sulphonamidehydrochloride

A solution of 0.55 g ofN-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3′-methyl2-N-amino-[1,1′-diphenyl]-3-sulphonamide (1 mmol) in 3 ml of ethylorthoformate is heated at 125° C. with stirring and under argon for 7 h.The reaction medium is then poured into a solution of 50 ml of aceticacid and 50 ml of water and heated at 100° C. for 1 h. After evaporationunder reduced pressure, the residue is taken up in 100 ml of ethylacetate, washed with 50 ml of saturated sodium chloride solution anddried over Na₂SO₄. The solvent is evaporated off under reduced pressureand the residue is taken up in 10 ml of a 0.1 N solution of hydrogenchloride in isopropanol and evaporated under reduced pressure. Theproduct is then chromatographed on RP18 silica in an N/100 hydrochloricacid/acetonitrile mixture of from 0 to 100% acetonitrile. 0.22 g of thedesired product is thus obtained.

Yield (%)=37; m.p. (°C.)=168;

[α]_(D) ²⁰ (°)=+108 (c=0.2; methanol)

EXAMPLE 10 (COMPOUND 123)N-[2-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl]-6-(2-thienyl)phenyl]acetamidehydrochloride

10.1 Methyl(2S)-2-[2,2-dimethyl-1-oxopropoxy)amino]-5-nitro-2-pyridyl)-4-pentynoate

18.3 ml (105.2 mmol) of diisopropylethylamine are added to a solution of11.95 g (52.6 mmol) of methyl(2S)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentynoate and 10 g (63.1mmol) of 2-chloro-5-nitropyridine in 100 ml of dichloromethane, followedby addition of 380 mg (2.6 mmol) of copper bromide. The medium isdegassed by bubbling argon through for 15 min. 740 mg (1.05 mmol) oftetrakis(triphenylphosphine)palladium (0) are added, under argon, to thereaction medium which is then refluxed (temperature=40° C.) for 4 h. Themedium turns black. The dichloromethane is evaporated off and theresidue is then taken up in 500 ml of ethyl acetate. The organic phaseis washed with saturated sodium chloride solution, dried over anhydroussodium sulphate and then evaporated to dryness. The evaporation residueis purified on silica with a cyclohexane/ethyl acetate mixture (85/15).16.6 g of a brown powder are obtained.

Yield (%)=90

10.2 Methyl(2S)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentynoate

A mixture of 11.6 g (33.2 mmol) of methyl(2S)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-5-nitro-2-pyridyl)-4-pentynoate,6.5 g (116.2 mmol) of iron, 100 ml of water, 200 ml of ethanol and 20 mlof acetic acid is refluxed for 5 h. The ethanol is evaporated off andthe medium is then filtered through Celite. The product is extractedwith dichloromethane. The organic phase is dried over anhydrousmagnesium sulphate and then evaporated to dryness. The evaporationresidue is purified on silica with a dichloromethane/methanol mixture(97/3). 8 g of a brown oil are obtained.

Yield (%)=80

10.3 Methyl(2S,4Z)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentenoate

4 g (12.5 mmol) of methyl(2S,4Z)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentynoatedissolved in 100 ml of ethyl acetate are placed in Parr apparatus andhydrogenated at room temperature at a pressure of 8 psi, for 4 h. Themixture is filtered through Whatman paper and the filtrate isevaporated. The crude residue is purified on silica with acyclohexane/ethyl acetate mixture (1/1). 1.8 g of a light brown powderare obtained.

Yield (%)=45

10.4(2S,4Z)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentenoicacid

260 mg of lithium hydroxide (6.16 mmol) are added to a solution ofmethyl(2S,4Z)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentenoate(1.8 g, i.e. 5.6 mmol) in a methanol/water mixture (45/15). The mixtureis left stirring overnight at room temperature. The medium is evaporatedto dryness by azeotropic distillation of the toluene. 1.6 ml of 4Nhydrogen chloride in dioxane and 30 ml of dichloromethane are added tothe medium. The resulting medium is again evaporated to dryness. Theexpected compound is obtained quantitatively in the form of an orangegum.

10.56-(1Z,4S)-5-[4-(difluoromethylene)-1-piperidyl]-4-[2,2-dimethyl-1-oxopropoxy)amino]-5-oxo-1-pentenyl-3-pyridinamine

2.82 ml (16.1 mmol) of diisopropylethylamine are added, under argon, toa solution of 1.07 g (6.2 mmol) of 4-difluoromethylenepiperidine in adichloromethane/dimethylformamide mixture (8/2). The medium is cooled to0° C. At this temperature, 2.2 g (6.2 mmol) of(2S,4Z)-5-(5-amino-2-pyridyl)-2-[(2,2-dimethyl-1-oxopropoxy)amino]-4-pentenoicacid and 2.2 g (6.93 mmol) of TBTU are added. The mixture is allowed towarm to room temperature with stirring overnight. The medium isevaporated to dryness and the residue is taken up in ethyl acetate andwashed with saturated sodium carbonate solution. The organic phase isdried over anhydrous sodium sulphate and evaporated to dryness. Theevaporation residue is purified on silica with a cyclohexane/ethylacetate/methanol mixture (45/45/10).

Yield (%)=75.

10.6N-[2-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl]-6-(2-thienyl)phenyl]acetamidehydrochloride

46 mmol (11.5 ml) of 4N hydrogen chloride in dioxane are added to asolution of 1.95 g (4.6 mmol) of6-(1Z,4S)-5-[4-(difluoromethylene)-1-piperidyl]-4-[2,2-dimethyl-1-oxopropoxy)amino]-5-oxo-1-pentenyl-3-pyridinaminein 40 ml of dichloromethane. The medium is left stirring overnight atroom temperature. The medium is evaporated to dryness. 351 mg (0.98mmol) of the residue are taken up in 3 ml of dichloromethane and 401 μl(2.94 mmol) of triethylamine are added thereto. The medium is cooled to0° C. At this temperature, 350 mg (0.98 mmol) of2-[(diacetylamino)-1,1′-diphenyl]-3-sulphonyl chloride are added. Themixture is allowed to warm to room temperature with stirring over 1 h.The medium is washed with aqueous sodium chloride solution and thenevaporated to dryness. The residue is taken up in 5 ml oftetrahydrofuran. Ammonia is bubbled through the medium, cooled to 0° C.,for 45 min. The tetrahydrofuran is evaporated off and the product isthen purified on silica with a cyclohexane/ethyl acetate mixture (3/7)and then on a reverse phase using an N/100 hydrochloricacid/acetonitrile gradient of from 0% to 100% acetonitrile.

Yield (%)=20; m.p. (°C.)=170;

[α]_(D) ²⁰ (°)=+40 (c=0.2; methanol)

EXAMPLE 11 (COMPOUND 121)N-[3-[[[(1S,3E)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl[1,1′-diphenyl]-2-yl-acetamidehydrochloride

11.1 Methyl (2S)-2-[(triphenylmethylamino]-4-pentynoate

22 ml (88 mmol) of 4N hydrogen chloride in dioxane are added to asolution of 2 g (8.8 mmol) of methyl(S)-2-[[1,1-dimethylethoxy)carboxy]amino]pent-4-ynoate in 5 ml ofdichloromethane. The mixture is left stirring for 2 h at roomtemperature. The medium is evaporated to dryness and then taken up in 8ml of dichloromethane. 1.8 ml (13.2 mmol) of triethylamine are addedthereto. The medium is cooled to 0° C. At this temperature, 2.6 g (0.65mmol) of trityl chloride are added thereto. The mixture is allowed towarm to room temperature with stirring overnight. The medium is washedwith water, dried over anhydrous sodium sulphate and then evaporated todryness. The evaporation residue is purified on silica with acyclohexane/ethyl acetate mixture (9/1). 3 g of a viscous white solidare obtained.

Yield (%)=92.

11.2 Methyl(2S)-5-(tributylstannyl)-2-[(triphenylmethyl)amino]-4-pentenoate

Argon is bubbled through a solution of 200 mg (0.54 mmol) of methyl(2S)-2-[(triphenylmethylamino]-4-pentynoate in 2 ml of anhydroustetrahydrofuran, for 10 min. 5% tetrakis(triphenylphosphine)palladium(0) (3 mg; 2.7×10⁻³ mmol) is added. When the medium is homogeneous, itis cooled to 0° C. 173 μl (0.65 mmol) of tributyltin hydride are addeddropwise at 0° C., under argon. The medium turns an opaque yellow. Themedium is allowed to warm to room temperature with stirring over 2 h.The medium is evaporated to dryness and then purified on Florisil®,eluting with pure cyclohexane. A transparent viscous liquid is obtained.

11.3 Methyl(2S,4E)-5-(5-nitro-2-pyridyl)-2-[(triphenylmethyl)amino]-4-pentenoate

Argon is bubbled through a solution of 80 mg (0.13 mmol) of methyl(2S)-5-(tributylstannyl)-2-[(triphenylmethyl)amino]-4-pentenoate and39.5 mg (0.19 mmol) of 2-bromo-5-nitropyridine in 1 ml of anhydrousdioxane, for 10 min. 11.4 mg (0.0125 mmol) oftetrakis(triphenylphosphine)palladium (0) are then added. The medium ismaintained at 110° C. for 24 h, under argon. The medium is washed withsaturated potassium fluoride solution and then extracted with ethylacetate. The organic phase is dried over anhydrous sodium sulphate andthen concentrated under reduced pressure. The evaporation residue ispurified on silica with a 98/2 and then 95/5 cyclohexane/ethyl acetatemixture. 20 mg of a yellow oil are obtained.

Yield (%)=31.

11.4 Methyl(2S,4E)-5-(5-amino-2-pyridyl)-2-[(triphenylmethyl)amino]-4-pentenoate

A mixture of 1.2 g (2.43 mmol) of methyl(2S,4E)-5-(5-nitro-2-pyridyl)-2-[(triphenylmethyl)amino]-4-pentenoate,477 mg (8.5 mmol) of iron, 3.6 ml of water, 7.2 ml of ethanol and 720 μlof acetic acid is maintained at 110° C. for 40 min. The medium isfiltered through Celite. The ethanol is evaporated off under reducedpressure. The crude residue is extracted with adichloromethane/isopropanol mixture (75/25). The organic phase is driedover anhydrous sodium sulphate and then concentrated under reducedpressure. The evaporation residue is purified on silica with acyclohexane/ethyl acetate mixture (6/4). 500 mg of a yellow oil areobtained.

Yield (%)=41.6.

11.5 Methyl(2S,4E)-2-[(2,2-dimethyl-1-oxopropoxylamino]-5-[5-[2,2-dimethyl-1-oxopropyl)amino]-2-pyridyl]-4-pentenoate

A solution of 500 mg (1.08 mmol) of methyl(2S,4E)-5-(5-amino-2-pyridyl)-2-[(triphenylmethyl)amino]-4-pentenoate in3.24 ml of hydrochloric acid and 2 ml of tetrahydrofuran is refluxed at65° C. for 1 h 30 min. The medium is allowed to cool. 1N sodiumhydroxide is added to the medium until the pH is basic. 2.35 g (10.8mmol) of di-tert-butyl carbonate are added thereto. The medium is leftstirring at room temperature for 24 h. The medium is washed with diethylether and then re-acidified with citric acid and the crude product isextracted with dichloromethane. The organic phase is dried overanhydrous sodium sulphate and then evaporated to dryness. 300 mg of ayellow oil are obtained.

Yield (%)=60.

11.6N-(1S,3E)-1-[[4-difluoromethylene)-1-piperidyl)carbonyl]-4-[5-(2,2-dimethyl-1-oxopropyl)amino]-2-pyridyl]-3-butenyl]-2,2-dimethylpropanamide

300 mg (0.73 mmol) of methyl(2S,4E)-2-[(2,2-dimethyl-1-oxopropylamino]-5-[5-[2,2-dimethyl-1-oxopropyl)amino]-2-pyridyl]-4-pentenoateare added to a solution, cooled to 0° C., of 120 mg (0.73 mmol) of4-difluoromethylenepiperidine in 8 ml of dichloromethane and 509 μl ofdiisopropylethylamine, followed by addition of 257 mg (0.80 mmol) ofTBTU. The medium is left stirring at 0° C. for 2 h 30 min. Thedichloromethane is evaporated off. The residue is taken up in ethylacetate, washed with saturated sodium carbonate solution and then withwater, and dried over anhydrous sodium sulphate. The organic phase isconcentrated under vacuum. The evaporation residue is purified on silicawith a dichloromethane/methanol mixture (99/1). 342 mg of a yellow oilare obtained.

Yield (%)=89.7.

11.7N-[3-[[[(1S,3E)-4-(5-amino-2-pyridyl)-1-[[4-difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl][1,1′-diphenyl]-2-yl-acetamidehydrochloride

4.6 ml (6.6 mmol) of 4N hydrogen chloride in dioxane are added to asolution of 342 mg (0.66 mmol) ofN-(1S,3E)-1-[[4-difluoromethylene)-1-piperidyl)carbonyl]-4-[5-(2,2-dimethyl-1-oxopropyl)amino]-2-pyridyl]-3-butenyl]-2,2-dimethylpropanamidein 4 ml of dichloromethane. The medium is stirred at room temperaturefor 2 h. The medium is evaporated to dryness. The evaporation residue istaken up in 3 ml of dichloromethane. 315 μl (2.31 mmol) of triethylamineare added thereto. The medium is cooled to 0° C. At this temperature,232 mg (0.66 mmol) of 2-(diacetylamino)-[1,1-diphenyl]-3-sulphonylchloride are added. The medium is allowed to warm to room temperaturewith stirring over 2 h. The medium is washed with saturated sodiumchloride solution. The organic phase is dried over anhydrous sodiumsulphate and then evaporated to dryness. The residue is taken up in 4 mlof tetrahydrofuran and cooled to 0° C. Ammonia is bubbled through over45 min at 0° C. The mixture is evaporated to dryness. The evaporationresidue is purified on silica with a cyclohexane/ethyl acetate mixture(2/8) and then on a reverse phase using an N/100 hydrochloricacid/acetonitrile gradient of from 0 to 100% acetonitrile. 150 mg of theexpected compound are obtained.

Yield (%)=38; m.p. (°C.)=175;

[α]_(D) ²⁰ (°)=+76 (c=0.1; methanol)

EXAMPLE 12 (COMPOUND 126)(S)-N-[3-[[[3-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]propyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamidehydrochloride

12.1 Phenylmethyl (S)-4-iodo-2-[[(phenylmethoxy)carbonyl]amino]butanoate

14 g (43 mmol) of di(acetyloxy)iodobenzene and 10.5 g (41 mmol) ofiodine are added to a solution of 30 g (80 mmol) of 1-phenylmethyl(L)-(N)-[(phenylmethoxy)carbonyl]glutamate in 800 ml of carbontetrachloride, under argon. The mixture is refluxed under UVirradiation. After 1 h 30 min, a further 14 g (43 mmol) ofdi(acetyloxy)iodobenzene and 10.5 g of iodine are added. After UVirradiation for 2 h, the mixture is washed with 10% sodium hydrogensulphite solution (2×300 ml), then with 200 ml of saturated sodiumhydrogen carbonate solution and then with 200 ml of water. The mixtureis dried over sodium sulphate, concentrated under reduced pressure andpurified by filtration through a column of silica gel, eluting with a95/5 cyclohexane/ethyl acetate mixture. 12.8 g of phenylmethyl(S)-4-iodo-2-[[(phenylmethoxy)carbonyl]amino]butanoate are obtained inthe form of an oil.

Yield (%)=35.

12.2 Phenylmethyl(S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate

A suspension of 6 g (92 mmol) of zinc powder and 0.4 ml (4.7 mmol) of1,2-dibromoethane in 7 ml of anhydrous N,N-dimethylformamide is heatedat 60° C. with stirring and under argon for 45 min. 0.126 ml (1 mmol) oftrimethylsilyl chloride is then added and the mixture is stirredvigorously at room temperature for 30 min. A solution of 7 g (15.4 mmol)of phenylmethyl (S)-4-iodo-2-[[(phenylmethoxy)carbonyl]amino]butanoatein 1 ml of anhydrous N,N-dimethylformamide is then added. After 30 minat room temperature, 0.28 g (0.31 mmol) oftris(dibenzylideneacetone)dipalladium (0), 0.38 g (1.24 mmol) oftri-ortho-tolylphosphine, 3.78 g (18.5 mmol) of 2-bromo-5-nitropyridineand 1 ml of anhydrous N,N-dimethylformamide are added at roomtemperature and the mixture is stirred for 3 h at room temperature. Thereaction medium is taken up in 200 ml of ethyl acetate and 5 g of activecharcoal and then filtered through a cake of Celite. The cake is rinsedwith 2×100 ml of ethyl acetate and the organic phases are combined,washed with 5×100 ml of water, dried over sodium sulphate andconcentrated under reduced pressure. The residue is purified byfiltration on a column of silica gel, eluting with a cyclohexane/ethylacetate gradient of from 0 to 20% ethyl acetate. 5.16 g of phenylmethyl(S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate arethus obtained in the form of a yellow foam.

Yield (%)=74.

12.3 (S)-α,5-diamino-2-pyridinebutanoic acid

A mixture of 5.16 g (11.5 mmol) of phenylmethyl(S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate, 2 gof active charcoal and 0.77 g of active palladium-on-charcoal in 100 mlof methanol and 100 ml of water is stirred for 4 days at 50 psi ofhydrogen at room temperature. The reaction medium is filtered through acake of Celite and the cake is rinsed with 3×50 ml of boiling water. Theaqueous phases are combined and concentrated under reduced pressure.2.05 g of (S)-α,5-diamino-2-pyridinebutanoic acid are thus obtained inthe form of a white solid.

Yield (%)=92; m.p. (°C.) >260.

12.4 (S)-α,5-bis[[(1,1-dimethylethoxy)carbonyl]amino]-2-pyridinebutanoicacid

1.05 ml (9.19 mmol) of aqueous 35% sodium hydroxide solution and 2 g(9.17 mmol) of bis(1,1-dimethylethyl)dicarbonate are added to a solutionof 0.85 g (4.36 mmol) of (S)-α,5-diamino-2-pyridinebutanoic acid in 50ml of water and 50 ml of 1,1-dimethylethanol. The solution is stirredfor 2 h at room temperature and a further 2 g (9.17 mmol) ofbis(1,1-dimethylethyl) dicarbonate and 1 ml of aqueous 35% sodiumhydroxide solution are added. After stirring for 15 h at roomtemperature, the reaction medium is diluted with 100 ml of aqueous 1Nsodium hydroxide solution and 50 ml of saturated sodium chloridesolution and then washed with 2×300 ml of ether. The aqueous phase isacidified with citric acid to pH=4-5 and then extracted with a 75/25dichloromethane/isopropanol mixture (2×100 ml). The organic phases arecombined and concentrated under reduced pressure. The residue is takenup in 100 ml of toluene and concentrated again under reduced pressure.1.18 g of(S)-α,5-bis[[(1,1-dimethylethoxy)carbonyl]amino]-2-pyridinebutanoic acidare obtained in the form of a viscous oil.

Yield (%)=69

12.5 1,1-dimethylethyl(S)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-3-[5-[[(1,1-dimethylethoxy)carbonyl]amino]2-pyridyl]propyl]carbamate

1.16 g (3.6 mmol) of O-(1-benzotriazolyl)-N,N,N′, N′-tetramethyluroniumtetrafluoroborate (TBTU) are added, under argon and with stirring at 0°C., to a mixture of 1.18 g (3 mmol) of(S)-α,5-bis[[(1,1-dimethylethoxy)carbonyl]amino]-2-pyridinebutanoicacid, 1.15 ml (6.6 mmol) of N,N-diisopropylethylamine and 0.56 g (3.3mmol) of 4-difluoromethylene-1-piperidine hydrochloride in 30 ml ofdichloromethane. The mixture is allowed to warm to room temperature andstirring is continued for 2 h. The reaction medium is diluted with 50 mlof dichloromethane and washed with 50 ml of water and then with 50 ml ofsaturated sodium hydrogen carbonate solution and again with 2×50 ml ofwater. The organic phase is dried over sodium sulphate and concentratedunder reduced pressure, and the residue is purified by chromatography ona column of silica gel, eluting with a 1/1 cyclohexane/ethyl acetatemixture. 1.62 g of 1,1-dimethylethyl(S)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-3-[5-[[(1,1-dimethylethoxy)carbonyl]amino]2-pyridyl]propyl]carbamateare obtained in the form of a viscous oil.

Yield (%)=100

12.6(S)-5-amino-α-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-2-pyridinepropanaminehydrochloride

A solution of 1.62 g (3.18 mmol) of 1,1-dimethylethyl(S)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-3-[5-[[(1,1-dimethylethoxy)carbonyl]amino]2-pyridyl]propyl]carbamatein 50 ml of dichloromethane is treated for 5 min at 0° C. with a streamof hydrogen chloride. The solution is allowed to warm to roomtemperature and stirring is continued for 3 h. The white precipitateobtained is then filtered off and rinsed with 10 ml of dichloromethane.1 g of highly hygroscopic(S)-5-amino-α-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-2-pyridinepropanaminehydrochloride (2:1) is thus obtained, and is used without furtherpurification in the following step.

Yield (%)=88; m.p. (°C.)=70

12.7(S)-N-[3-[[[3-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]propyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamidehydrochloride

0.8 ml (5.7 mmol) of triethylamine is added to a solution of 0.7 g (1.83mmol) of(S)-5-amino-α-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-2-pyridinepropanaminehydrochloride (2:1) in 20 ml of dichloromethane, and the resultingsolution is cooled to 0° C. with stirring. 0.58 g (1.64 mmol) of2-(diacetylamino)-[1,1′-diphenyl]-3-sulphonyl chloride is then addedportionwise. After 2 h at 0° C., 50 ml of dichloromethane are added andthe solution is washed successively with 2×20 ml of water, 50 ml ofsaturated sodium hydrogen carbonate solution and 2×10 ml of water. Theorganic phase is dried over sodium sulphate and concentrated underreduced pressure. The residue obtained is taken up in 20 ml oftetrahydrofuran and is then cooled to 0° C. and treated for 5 min with astream of ammonia. The reaction mixture is allowed to warm to roomtemperature and, after 4 h, is then concentrated under reduced pressure.The residue obtained is purified by chromatography on a column of silicagel, eluting under pressure with a 99/1 dichloromethane/methanolmixture. After concentration under reduced pressure, the residue is thentaken up in 1.8 ml of a 1M solution of hydrogen chloride in methanol(1.8 mmol) and is again concentrated under reduced pressure and thenpurified by chromatography on an RP18 column, eluting with anacetonitrile/N/1000 hydrochloric acid gradient of from 5/95 to 100/0over 60 min. After lyophilization, 0.61 g of(S)-N-[3-[[[3-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]propyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamidehydrochloride is obtained in the form of a white powder.

Yield (%)=60; m.p. (°C.)=184-186;

[α]_(D) ²⁰ (°)=+118 (c=0.23; methanol)

Key to the tables which follow:

in the “salt” column, “HCl” corresponds to a hydrochloride and the ratioin parentheses is the (acid:base) ratio,

in the “[α]_(D) ²⁰” column, c=0.2; methanol except for compounds 9 and11 (c=0.4; methanol).

TABLE 1 (I₁)

Melting point [α]_(D) ²⁰ No. R₃ X A R₂ B Salt (° C.) (° )  1 —COCH₂CH₃CH

HCl (1:1) 155-159  +89  2 —COCH₂CH₃ CH

HCl (1:1) 128-133  +86  3 —COCH₂CH₃ CH

HCl (1:1) 144-148 +120  4 —COCH₂CH₃ CH

HCl (1:1) 145-150 +110  5 —COCH₂CH₃ CH

HCl (2:1) 145-150 +138  6 —COCH₂CH₃ CH

HCl (1:1) 136-140 +103  7 —COCH₂CH₃ CH

HCl (1:1) 140-144  +60  8 —COCH₂CH₃ CH

HCl (1:1) 122-126  +83  9 —COCH₂CH₃ CH

HCl (1:1) 112 +114  10 —COCH₂CH₃ CH

HCl (1:1) 134-138 +112  11 —COCH₂CH₃ CH

HCl (1:1) 116 +102  12 —COCH₂CH₃ CH

HCl (1:1) 144-148 +102  13 —COCH₂CH₃ CH

HCl (1:1) 158-162  +80  14 —COCH₂CH₃ CH

HCl (1:1) 135-140 +108  15 —COCH₂CH₃ CH

HCl (1:1) 142-146 +103  16 —COCH₂CH₃ CH

— 154-158 +123  17 —COCH₂CH₃ CH

HCl (1:1) 146-150 +139  18 —COCH₂CH₃ CH

HCl (1:1) 143-147  +62  19 —COCH₂CH₃ CH

HCl (1:1) 132-136  +93  20 —COCH₂CH₃ CH

HCl (1:1) 142-146 +111  21 —COCH₂CH₃ CH

HCl (1:1) 145-149 +128  22 —COCH₂CH₃ CH

HCl (1:1) 140-144  +97  23 —COCH₂CH₃ CH

HCl (1:1) 152-156  +82  24 —COCH₂CH₃ CH

HCl (1:1) 136-140  +90  25 —COCH₂CH₃ CH

HCl (1:1) 146-150  +76  26 —COCH₂CH₃ CH

HCl (1:1) 146-150 +101  27 —COCH₂CH₃ CH

HCl (1:1) 142-146  +65  28 —COCH₂CH₃ CH

HCl (1:1) 150-154  +66  29 —COCH₂CH₃ CH

HCl (1:1) 160-164  +69  30 —COCH₂CH₃ CH

HCl (1:1) 150-154  +72  31 —COCH₂CH₃ CH

HCl (1:1) 149-152 +118  32 —COCH₂CH₃ CH

HCl (1:1) 146-150    155  33 —COCH₂CH₃ CH

HCl (1:1) 143-147  +56  34 —COCH₂CH₃ CH

HCl (1:1) 144-148  +95  35 —COCH₂CH₃ CH

HCl (1:1) 146-150  +77  36 —COCH₂CH₃ CH

HCl (1:1) 147-151 +122  37 —COCH₂CH₃ CH

HCl (1:1) 159-163 +114  38 —COCH₂CH₃ CH

HCl (1:1) 150-156  +65  39 —COCH₃ CH

HCl (1:1) 188-192  +64  40 —COCH₂CH₃ CH

HCl (1:1) 153-157  +74  41 —COCH₂CH₃ CH

HCl (1:1) 166-170  +95  42 —COCH₂CH₃ CH

HCl (1:1) 172-176  +62  43 —COCH₃ CH

HCl (1:1) 138-142  +85  44 —COCH₂CH₃ CH

HCl (1:1) 157-161 +102  45 —COCH₂CH₃ CH

HCl (1:1) 156-160  +86  46 —COCH₂CH₃ CH

HCl (1:1) 163-167  +70  47 —COCH₃ CH

HCl (1:1) 152-156  +92  48 —COCH₃ CH

HCl (1:1) 154-158  +91  49 —COCH₂CH₃ CH

HCl (1:1) 154-158  +78  50 —COCH₃ CH

HCl (1:1) 156-160  +91  51 —COCH₃ CH

HCl (1:1) 148-152  +79  52 —COCH₃ CH

HCl (1:1) 170-174  +90  53 —COCH₂CH₃ CF

HCl (1:1) 150-154  +88  54 —COCH₃ CH

HCl (1:1) 170-172 +132  55 —COCH₃ CH

HCl (1:1) 166-168 +122  56 —COCH₃ CH

HCl (1:1) 160-162  +82  57 —COCH₂CH₃ CF

HCl (1:1) 150-154  +39  58 —COCH₂CH₃ CF

HCl (1:1) 148-152  +90  59 —COCH₃ CH

HCl (1:1) 148-152  +77  60 —COCH₂CH₃ CH

HCl (1:1) 154-158 +106  61 —COCH₂CH₃ CH

HCl (1:1) 144-148  +91  62 —COCH₂CH₃ CH

HCl (1:1) 158  +78  63 —COCH₃ CH

HCl (1:1) 162 +110  64 —COCH₂CH₃ CH

HCl (1:1) 148  +86  65 —COCH₃ CH

HCl (1:1) 148-152  +81  66 —COCH₂CH₃ CH

HCl (1:1) 146-150  +67  67 —COCH₂CH₂CH₃ CH

HCl (1:1) 140-144 +102  68 —COCH₃ CH

HCl (1:1) 150-154  +59  69 —COCH₂CH₃ CH

HCl (1:1) 154-155  +85  70 —COCH₂CH₃ CH

HCl 139-140 +100  71 —COCH₃ CH

HCl 176-180  +84  72 —COCH₂CH₃ CH

HCl 178-182  +71  73 —COCH₂CH₃ CH

HCl 138-139 +155  74 —COCH₃ CH

HCl 145-146 +116  75 —COCH₂CH₃ CH

HCl 146-147  +62  76 —COCH₃ CH

HCl 156-157  +84  77 —COCH₃ CH

HCl 147-148 +136  78 —COCH₃ CH

HCl 168  +83  79 —COCH₃ CH

HCl 164  +63  80 —COCH₂CH₃ CH

HCl 152 +112  81 —COCH₂CH₃ CH

HCl 160 +107  82 —COCH₂CH₃ CH

HCl 155-157 +130  83 —COCH₃ CH

HCl 159-161 +106  84 —COCH₂CH₃ CH

HCl 160-164 +105  85 —COCH₂CH₃ CH

HCl 180-184  +88  86 —COCH₂CH₃ CH

HCl 230-234 +100  87 —COCH₂CH₃ CH

HCl 153-157  +74  88 —COCH₂CH₃ CH

HCl 144-148  +77  89 —COCH₂CH₃ CH

HCl 160-164  +66  90 —COCH₂CH₃ CH

HCl 150-154  +87  91 —COCH₂CH₃ CBr

HCl 166-170  +76  92 —COCH₂CH₃ CH

HCl 160-164 +100  93 —COCH₂CH₃ CH

HCl 152-156  +82  94 —COCH₃ CH

HCl 162-166 +101  95 —COCH₃ CH

HCl 148-152  +57  96 —COCH₃ CH

HCl 145-149  +64  97 —COCH₃ CBr

HCl 168-172  +50  98 —COCH₃ CH

HCl 153-158 +191  99 —COCH₂CH₃ CH

HCl 72-76  +50 100 —COCH₂CH₃ CH

HCl 145-149  +47 101 —COCH₂CH₃ CH

— 139 +127 102 —COCH₂CH₃ CH

HCl 134 +114 103 —COCH₂CH₃ CH

HCl 137 +122 104 —COCH₂CH₃ CH

— 139 +132 105 —COCH₂CH₃ CH

HCl 173-177 +108 106 —COCH₂CH₃ CH

HCl 170-174 +129 107 —COCH₂CH₃ CH

HCl 160-164 +124 108 —COCH₂CH₃ CH

HCl 162-164 +120 109 —COCH₂CH₃ CH

HCl 142-146  +87 110 —COCH₂CH₃ CH

HCl 162-166 +116 111 —COCH₂CH₃ CH

HCl 165-169  +94.5 112 —COCH₂CH₃ CH

HCl 156-160  +83 113 —COCH₂CH₃ CH

HCl 158-162 +109 114 —COCH₂CH₃ N

HCl 180-184 +100 115 —COCH₂CH₃ N

HCl 178-182  +85 116 —COCH₂CH₃ N

HCl (2:1) 190-194  +73 117 —COCH₂CH₃ N

HCl (1.5:1) 180-184  +91 118 —CHO CH

HCl 168 +108

TABLE 2 (I₂)

Melting point [α]_(D) ²⁰ No. R₃ X A R₂ B Salt (° C.) (°) 119 —COCH₃ CH

HCl 166 +52

TABLE 3 (I₃)

with R₃ = —COCH₃ and X = CH Configuration of the double Melting point[α]_(D) ²⁰ No. bond A R₂ B Salt (° C.) (°) 120 cis

HCl 161  +68 121 trans

HCl 175  +76 122 cis

HCl 119 +134 123 cis

HCl 170  +40 124 trans

HCl 173.5  +87 125 trans

— — —

TABLE 4 (I₄)

Melting point [α]_(D) ²⁰ No. R₃ X A R₂ B Salt (° C.) (°) 126 —COCH₃ CH

HCl 184-6 +118 (c = 0.23)

The compounds of the invention underwent pharmacological studies whichdemonstrated their antithrombotic and anticoagulant properties, andtheir value as therapeutically active substances.

1. Determination of the Inhibition Constants (Ki) with Respect toThrombin (In vitro)

25 μl of a solution of test compound (7 concentrations are studied), 50μl of a solution of chromogenic substrate (2 concentrations are studied;S2238 Chromogenix™) dissolved in Tris buffer at pH 7.5 (50 mM Tris, 100mM NaCl and 0.1% BSA) and finally 25 μl of a 0.24 U/ml thrombin solutionare placed in each well of a 96-well microplate. The release of4-nitroaniline is monitored at 405 nm using a plate reader.

The K_(i) is determined by the Dixon method.

The compounds of the invention inhibit human thrombin and their K_(i) isbetween 0.001 and 100 μM.

2. Anticoagulant Activity on Rat Plasma (Ex vivo)

Male CD rats weighing 200 to 250 g are treated with the test compound orwith its vehicle orally. The animals are then anaesthetized withNembutal™ (60 mg/kg; 0.1 ml/kg), blood is collected over 3.8% trisodiumcitrate (1 vol/9 vol of blood) from the retro-orbital sinus and theplasma is prepared by centrifugation at 3000×g for 15 minutes at roomtemperature. 200 μl of plasma are then incubated at 37° C. with 200 μlof thrombin solution, the final thrombin concentration being 0.75 NIHunits/ml, and the clotting time is noted.

The anticoagulant effect is expressed as a percentage increase in thethrombin time on the plasmas collected 30 and 90 minutes afteradministering 20 mg/kg p.o.; it is between 100 and 2000%.

3. Antithrombotic Activity in Rats in a Model of Mixed Arterio-venousThrombosis (In vivo)

The formation of a thrombus in rats is obtained by placing a shuntbetween the left jugular vein and the right carotid artery; cottonthread impregnated with thromboplastin (Tissue Factor or TF) is insertedinto the shunt. The compound is administered orally in several doses 30or 60 minutes before installing the shunt. Five minutes after installingthe shunt, the thrombus formed on contact with the thread +TF is removedand rapidly weighed. The antithrombotic activity is evaluated by thereduction in the fresh weight of the thrombus (mg) in the animalstreated with the compound, compared with the control animals treatedwith its vehicle.

The antithrombotic activity is expressed as an AD₅₀, the dose whichreduces the weight of the fresh thrombus by 50% dependent. This dose isbetween 0.1 and 50 mg/kg.

4. Membrane Permeability In vitro

The compounds of the invention are evaluated in a model of membranepermeability on a Caco-2 cell line obtained from a human adenocarcinoma.This cell line constitutes a model of choice for studying the absorptionof xenobiotics [P. Artusson, Therapeutics Drug Carrier System (1991),8(4), pp 305-330]. The passage of the compounds of the invention isexpressed as a function of the amount of product which has crossed thecell barrier in 2 h. The values are between 0 and 50%.

The compounds of the invention may be useful in any clinical indicationassociated with thrombosis or in an indication in which thromboticcomplications may occur.

To this end, they may be provided in any form which is suitable fororal, parenteral or intravenous administration, such as plain tablets,coated tablets, gel capsules, wafer capsules, drinkable or injectablesuspensions or solutions, etc., in combination with suitable excipients.All these forms are dosed to allow an administration of from 1 to 1000mg per day and per patient, in one or more doses.

What is claimed is:
 1. A compound of formula (I):

wherein: X is a nitrogen atom or CR₄ in which R₄ is hydrogen or halogen;W is —CH₂)₂—, —(CH₂)₃—, —CH₂—C≡C— or —CH₂—CH═CH—, R₂ is: piperidyloptionally substituted: with one or two groups chosen from hydroxyl,(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)alkylthio, monofluoromethyl, difluoromethyl,trifluoromethyl and (C₃-C₆)cycloalkyl, with a group ═CYZ in which Y andZ are independently hydrogen, halogen or (C₁-C₄)alkyl optionallysubstituted with 1 to 3 halogen atoms, with a group

 in which r is 1 to 3, or with a spiro (C₃-C₆)cycloalkane group;1,2,3,6-tetrahydropyridyl optionally substituted with a (C₁-C₄)alkylgroup, said (C₁-C₄)alkyl group being optionally substituted with 1 to 3halogen atoms or a (C₃-C₆)cycloalkyl group; hexahydro-1H-azepinyloptionally substituted in position 4 with a trifluoromethyl ordifluoromethylene group; heptahydroazocin-1-yl;octahydro-1H-azonin-1-yl; a group

 in which a-b is —CONR′—, m=1 to 2, p=1 to 2 and R′ is hydrogen or(C₁-C₄)alkyl; a group

 in which R₁₂ is (C₁-C₄)alkyl, carboxy(C₁-C₄)alkyl or(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl and R₁₃ is (C₁-C₄)alkoxy or(C₁-C₄)alkyl, or R₁₂ is (C₁-C₄)alkyl or CH₂CF₃ and R₁₃ is a group

 in which Q is a carbon or nitrogen atom and r is 1 to 3; piperazinyloptionally substituted with (C₁-C₄)alkyl or (C₁-C₄)alkylsulphonyl; ormorpholinyl; R₃ is: (C₁-C₅)alkyl; or —COR₁, in which R₁ is hydrogen,(C₁-C₄)alkyl, —(CH₂)_(n)OCH₃, —CH₂O(C₂H₄O)_(n)CH₃, —(CH₂)_(n)CF₃ or—(CH₂)_(n)OH and n is 1 to 4; —SO₂R₅; —CONHR₅; or —SO₂N(R₅)₂, R₅ is(C₁-C₄)alkyl; A is: (C₅-C₈)cycloalkyl; or phenyl, pyridyl, thienyl,furyl, pyrimidinyl or thiazolyl, said groups optionally substituted with1 to 3 substituents chosen from halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,trifluoromethyl, trifluoromethoxy, —CH₂OR₁₀, —CH₂OCOR₁₀, —CH₂OCONR₁₀R₁₁,—COOR₁₀, —CONR₁₀R₁₁, nitro, —NR₁₀R₁₁, —NHCOR₁₀ and —NH(CH₂)_(q)OR₁₀, inwhich R₁₀ and R₁₁ are independently hydrogen or (C₁-C₄)alkyl and q isfrom 0 to 6; and B is: pyridyl optionally substituted with 1 or 2substituents chosen from (C₁-C₄)alkyl, hydroxyl and (C₁-C₄)alkoxy;aminopyrazinyl; aminopyridazinyl; pyrimidinyl optionally substitutedwith an amino group; piperidyl; aminopyridyl optionally substituted onthe pyridine with (C₁-C₄)alkyl, (C₁-C₄)alkoxy or halogen and optionallysubstituted on the amino group with (C₁-C₄)alkyl; aminophenyl optionallysubstituted on the amino group with (C₁-C₄)alkyl and on the phenyl groupwith (C₁-C₄)alkyl or halogen; or a pharmaceutically acceptableacid-addition salt thereof.
 2. A compound according to claim 1, whereinR₂ is: piperidyl optionally substituted with one or two groups chosenfrom hydroxyl, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,monofluoromethyl, difluoromethyl, trifluoromethyl and (C₃-C₆)cycloalkyl,or with a group ═CYZ in which Y and Z are independently hydrogen,halogen or (C₁-C₄)alkyl optionally substituted with 1 to 3 halogenatoms; 1,2,3,6-tetrahydropyridyl optionally substituted with a(C₁-C₄)alkyl group, said (C₁-C₄)alkyl group being optionally substitutedwith 1 to 3 halogen atoms or a (C₃-C₆)cycloalkyl group;hexahydro-1H-azepinyl optionally substituted in position 4 with atrifluoromethyl or difluoromethylene group; a group

 in which R₁₂ is (C₁-C₄)alkyl, carboxy(C₁-C₄)alkyl or(C₁-C₄)alkoxycarbonyl(C₁-C₄)alkyl and R₁₃ is (C₁-C₄)alkoxy or(C₁-C₄)alkyl; piperazinyl optionally substituted with (C₁-C₄)alkyl or(C₁-C₄)alkylsulphonyl; or morpholinyl; and R₃ is: (C₁-C₅)alkyl; or—COR₁, in which R₁ is hydrogen, (C₁-C₄)alkyl, —(CH₂)_(n)OCH₃,—CH₂O(C₂H₄O)_(n)CH₃, —(CH₂)_(n)CF₃ or —(CH₂)_(n)OH and n is 1 to
 4. 3. Acompound according to claim 1 wherein W is —(CH₂)₃— or —CH₂—CH═CH—; R₂is: piperidyl optionally substituted with one or two groups chosen fromhydroxyl, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-(C₄)alkylthio, monofluoromethyl, difluoromethyl and trifluoromethyl,or with a group ═CYZ in which Y and Z are independently hydrogen,halogen or (C₁-C₄)alkyl optionally substituted with 1 to 3 halogenatoms; 1,2,3,6-tetrahydropyridyl optionally substituted with(C₁-C₄)alkyl said (C₁-C₄)alkyl group being optionally substituted with 1to 3 halogen atoms; hexahydro-1H-azepinyl; piperazinyl optionallysubstituted with (C₁-C₄)alkylsulphonyl; or morpholinyl; R₃ is —COR₁, inwhich R₁ is (C₁-C₄)alkyl, —(CH₂)_(n)OCH₃ or —(CH₂)_(n)CF₃ and n is 1 to4; and A is: phenyl optionally substituted with 1 to 3 substituentschosen from halogen, —(C₁-C₄)alkyl and (C₁-C₄)alkoxy; a heterocyclechosen from pyridyl and thienyl groups; or (C₅-C₈)cycloalkyl.
 4. Acompound according to claim 2 wherein W is —(CH₂)₃— or —CH₂—CH═CH—; R₂is: piperidyl optionally substituted with one or two groups chosen fromhydroxyl, (C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy, (C₁-C₄)alkylthio, monofluoromethyl, difluoromethyl andtrifluoromethyl, or with a group ═CYZ in which Y and Z are independentlyhydrogen, halogen or (C₁-C₄)alkyl optionally substituted with 1 to 3halogen atoms; 1,2,3,6-tetrahydropyridyl optionally substituted with(C₁-C₄)alkyl said (C₁-C₄)alkyl group being optionally substituted with 1to 3 halogen atoms; hexahydro-1H-azepinyl; piperazinyl optionallysubstituted with (C₁-C₄)alkylsulphonyl; or morpholinyl; R₃ is —COR₁, inwhich R₁ is (C₁-C₄)alkyl, —(CH₂)_(n)OCH₃ or —(CH₂)_(n)CF₃ and n is 1 to4; and A is: phenyl optionally substituted with 1 to 3 substituentschosen from halogen, —(C₁-C₄)alkyl and (C₁-C₄)alkoxy; a heterocyclechosen from pyridyl and thienyl groups; or (C₅-C₈)cycloalkyl.
 5. Acompound selected from the group consisting of:—N-[2-[[[(1S)-4-(5-amino-3-methylpyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,—N-[2-[[[(1S)-4-(6-amino-4-ethylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6cyclopentylphenyl]acetamide,N-[3-[[[(1S)-4(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]propanamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]acetamide,N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-piperid-1-ylcarbonyl)butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]acetamide,N-[2-[[[(1S)-4-(6-amino-4-methylpyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide,N-[2-[[[(1S)-4(aminopyrid-3-yl)-1-[[4-(trifluoromethyl)-1,2,3,6-tetrahydropyrid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[[4(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]propanamide,N-[2-[[[(1S)-4-(6amino-4-methylpyrid-3-yl)-1-[[4-difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]propanamide,N-[3-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]propanamide,N-[2-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]acetamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-ethylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-thien-2-ylphenyl]propanamide,N-[2-[[[(1S)-4-(6-aminopyrid-3-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-6-cyclopentylphenyl]acetamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methyl[1,1′-diphenyl]-2-yl]acetamide,N-[3-[[[(1S)-4-(6amino-4-methoxypyrid-3-yl-1-[[4-(difluoromethylene)piperid-1-yl]carbonyl]butyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]propanamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methyl[1,1′-diphenyl]-2-yl]propanamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-fluoro[1,1′-diphenyl]-2-yl]acetamide,N-[3-[[[(1S)-4-(5-aminopyrid-2-yl)-1-[(4-methylpiperid-1-yl)carbonyl]butyl]amino]sulphonyl]-3′-methoxy[1,1′-diphenyl]-2-yl]propanamide,N-[(1S)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]butyl]-2-(formylamino)-3′-methyl[1,1′-diphenyl]-3-sulphonamide,N-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[[4-(difluoromethylene)-1-piperidyl]carbonyl]-3-butenyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide,andN-[3-[[[(1S,3Z)-4-(5-amino-2-pyridyl)-1-[(4-methyl-1-piperidyl)carbonyl]-3-butenyl]amino]sulphonyl][1,1′-diphenyl]-2-yl]acetamide,or a pharmaceutically acceptable acid-addition salt thereof.
 6. Acompound according to claim 1 wherein the asymmetric carbon atom informula I

had the S configuration.
 7. A compound according to claim 2 wherein theasymmetric carbon atom in formula I

had the S configuration.
 8. A compound according to claim 3 wherein theasymmetric carbon atom in formula I

had the S configuration.
 9. A compound according to claim 4 wherein theasymmetric carbon atom in formula I

had the S configuration.
 10. A process for preparing a compoundaccording to claim 1 in which X is CR₄— which comprises reacting acompound of formula (V)

in which P₁ is a protecting group and P is a protecting group orhydrogen with a compound of formula (VI) R₂H  (VI) to give a compound offormula (IV)

which is then treated with hydrogen chloride to give a compound offormula (III) as a hydrochloride salt

which, in turn is condensed with a compound of formula (II)

followed by a hydrogenolysis when it is desired to obtain a compound offormula (I) in which R₄ is hydrogen, A, B, W, R₁, R₂ and R₄ in the aboveformulas having the meanings given in claim
 1. 11. A process forpreparing a compound according to claim 1 in which X is CR₄— whichcomprises reacting a compound of formula (III) in which P represents ahydrogen atom

with a compound of formula (IIa)

to give a compound of formula (Ia)

which is then coupled with a compound of formula (VII) A—Sn(R₅)₃  (VII)in which R₅ is a (C₁-C₄)alkyl group, followed by a hydrogenolysis whenit is desired to obtain the compound of formula (I) in which R₄ ishydrogen, A, B, W, R₁, R₂ and R₄ in the above formulas having themeanings given in claim
 1. 12. A process for preparing a compoundaccording to claim 1 in which X is a nitrogen atom which comprisescoupling a compound of formula (III)

with a compound of formula (XV)

A, B, W, R₁ and R₂ having the meanings given in claim
 1. 13. A compoundof formula (III)

wherein B, W and R₂ are as defined in claim 1 and P is a protectinggroup or hydrogen, or a hydrochloride salt thereof.
 14. A compound offormula XV

in which A and R₁ are as defined in claim
 1. 15. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 1 together with a pharmaceutically acceptableexcipient.
 16. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 2 together with apharmaceutically acceptable excipient.
 17. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 3 together with a pharmaceutically acceptable excipient.
 18. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 4 together with a pharmaceuticallyacceptable excipient.
 19. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 5altogether with a pharmaceutically acceptable excipient.
 20. A methodfor the treatment of thrombosis which comprises administering to apatient in need of such treatment a therapeutically effective amount ofa compound according to claim
 1. 21. A method for the treatment ofthrombosis which comprises administering to a patient in need of suchtreatment a therapeutically effective amount of a compound according toclaim
 2. 22. A method for the treatment of thrombosis which comprisesadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound according to claim
 3. 23. A method forthe treatment of thrombosis which comprises administering to a patientin need of such treatment a therapeutically effective amount of acompound according to claim
 4. 24. A method for the treatment ofthrombosis which comprises administering to a patient in need of suchtreatment a therapeutically effective amount of a compound according toclaim
 5. 25. A method for the prevention of thrombus formation in apatient in need thereof which comprises administering to said patient ananticoagulation effective amount of a compound according to claim
 1. 26.A method for the prevention of thrombus formation in a patient in needthereof which comprises administering to said patient an anticoagulationeffective amount of a compound according to claim
 2. 27. A method forthe prevention of thrombus formation in a patient in need thereof whichcomprises administering to said patient an anticoagulation effectiveamount of a compound according to claim
 3. 28. A method for theprevention of thrombus formation in a patient in need thereof whichcomprises administering to said patient an anticoagulation effectiveamount of a compound according to claim
 4. 29. A method for theprevention of thrombus formation in a patient in need thereof whichcomprises administering to said patient an anticoagulation effectiveamount of a compound according to claim 5.